Certain 4-aryl-1,4-dihydro-3,5-pyridinedicarboxylates having vasodilating and anti-hypertensive properties

ABSTRACT

1,4-Dihydropyridine derivatives of the general formula   &lt;IMAGE&gt; having vasodilating and anti-hypertensive activity, processes for preparing same, and pharmaceutical compositions thereof for treating cardiovascular diseases.

This is a division of application Ser. No. 213,048, filed Dec. 4, 1980,now U.S. Pat. No. 4,370,334, which is a division of application Ser. No.39,752, filed May 17, 1979, now U.S. Pat. No. 4,284,634, which is acontinuation-in-part of application Ser. No. 809,788, filed June 24,1977, now abandoned, which is a continuation-in-part application of Ser.No. 701,994, filed July 1, 1976, now U.S. Pat. No. 4,145,432.

This invention relates to 1,4-dihydropyridine derivatives. Moreparticularly, it relates to new 1,4-dihydropyridine derivatives thereofwhich have vasodilating and anti-hypertensive activity, to processes forthe preparation thereof, and to pharmaceutical composition comprisingthe same for therapeutical treatment in cardiovascular deseases andhypertension in human being.

Accordingly, one object of this invention is to provide new and useful1,4-dihydropyridine derivatives.

Another object of this invention is to provide processes for thepreparation of 1,4-dihydropyridine derivatives.

A further object of this invention is to provide useful pharmaceuticalcomposition comprising said 1,4-dihydropyridine derivatives as avasodilator and anti-hypertensive.

Still further object of the present invention is to provide atherapeutical method of treating cardiovascular diseases such ascoronary insufficiency, angina pectoris or myocardial infarction andhypertension.

The 1,4-dihydropyridine derivatives of this invention may be representedby the general formula: ##STR2## wherein

R₁ is aryl which may have one or more suitable substituent(s) or aheterocyclic group,

R₂ and R₃ are each, same or different, esterified carboxy, and

R₄ and R₅ are each hydrogen; cyano; lower alkyl; or substituted loweralkyl in which the substituent is cyano, hydroxy, acyloxy, hydroxyimino,hydrazono, lower alkoxyimino, hydroxy(lower)alkylimino, N'- orN',N'-di-(lower)alkylamino(lower)alkylimino, hydrazino,hydroxy(lower)alkylamino, N'- orN',N'-di-(lower)alkylamino(lower)alkylamino, a 5 or 6-membered saturatedN-containing heterocyclic-1-yl which may have hydroxy, lower alkyl orhydroxy(lower)alkyl, or oxo wherein thus formed carbonyl may beprotected with suitable protecting group; provided that, when one of R₄and R₅ is hydrogen or lower alkyl, the other is always cyano or saidsubstituted lower alkyl, and when R₄ and R₅ are not hydrogen or loweralkyl, both of them are a group selected from cyano and said substitutedlower alkyl,

or R₄ is hydrogen or lower alkyl and R₃ and R₅ are combined to form agroup of the formula: ##STR3## wherein R₆ is hydrogen or methyl and R₇is 2-(N,N-diethylamino)ethyl or 2-hydroxyethyl.

The terms used in the definitions of the symbols of the general formulaegiven in this specification and claims are explained as follows:

The term "lower" used in connection with an alkylene, alkyl and alkenylis intended to mean the one having 1 to 8 carbon atoms.

Aryl and aryl moiety may be phenyl, naphthyl, xylyl, tolyl, mesityl,cumenyl and the like, which may have one or more suitablesubstituent(s). Preferred examples of the suitable substituents(s) arehalogen, nitro, hydroxy, halo(lower)alkyl, lower alkoxy, loweralkenyloxy, cyano, lower alkoxycarbonyl or lower alkylsulfamoyl. Halogenor halo moiety is fluorine, chlorine, bromine or iodine.

Lower alkylene may be one having a straight or branched and saturatedbivalent hydrocarbon chain such as methylene, ethylene, methylmethylene,trimethylene, propylene or tetramethylene.

Lower alkyl and lower alkyl moiety may be ones having a straight orbranched and saturated hydrocarbon chain such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, neo-pentyl, hexyl, heptylor octyl.

Lower alkoxy and lower alkoxy moiety may be methoxy. ethoxy, propoxy,isopropoxy, butyoxy, t-butoxy and pentyloxy.

Halo(lower)alkyl may be mono-halo(lower)alkyl such as chloromethyl,bromomethyl or chloropropyl; di-halo(lower)alkyl such as1,2-dichloroethyl, 1,2-dibromoethyl or 2,2-dichloroethyl; andtri-halo(lower)alkyl such as trifluoromethyl or 1,2,2-trichloroethyl.

Lower alkenyl and lower alkenyl moiety may be ones having a straight orbranched hydrocarbon chain which contains one or more double bond(s),such as vinyl, allyl, butenyl, butanedienyl or penta-2,4-dienyl.

Acyl and acyl moiety may be lower alkanoyl such as formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl;substituted lower alkanoyl, for example, carboxy(lower)alkanoyl,esterified carboxy(lower)alkanoyl such as loweralkoxycarbonyl(lower)alkanoyl, N- or N,N-di-substitutedamino(lower)alkanoyl such as N- orN,N-di-(lower)alkylamino(lower)alkanoyl (e.g. N-methyl (orN,N-dimetyl)aminoacetyl, 1(or 2-[N-ethyl(or N,N-diethyl)amino]propionylor 1(or 2)-[N-methyl-N-ethylamino]propionyl) or N-loweralkyl-N-ar(lower)alkylamino(lower)alkanoyl (e.g. 1-(or2)-[N-methyl-N-benzylamino[propionyl) or aryloxy(lower)alkanoyl such asphenoxyacetyl, tolyloxyacetyl, 2(or 3 or 4)-chlorophenoxyacetyl, 2-[2(or3 or 4)-chlorophenoxy]-propionyl, 2(or 3 or 4)-nitrophenoxyacetyl or2(or 3 or 4)-methoxyphenoxyacetyl); aroyl such as benzoyl, naphthoyl ortoluoyl and the like.

Lower alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyland the like.

Lower alkylsulfamoyl may be methylsulfamoyl, ethylsulfamoyl,propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl, pentylsulfamoyl andthe like.

A heterocyclic group for R₁ may be an aromatic heterocyclic groupcontaining one or more hetero atom(s) selected form nitrogen atom,sulfur atom and oxygen atom, for example, thienyl, furyl, pyrrolyl,thiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, quinolyl,isoquinolyl, benzothienyl, indolyl or purinyl.

Esterifed carboxy for R₂ and R₃ may be lower alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,t-butoxycarbonyl; halo(lower)alkoxycarbonyl such as the halo-analoguesof the above-mentioned lower alkoxycarbonyl (e.g.,2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2 (or3)-chloropropoxycarbonyl, 2 (or 3)-bromopropoxycarbonyl,2,2-dichloroethoxycarbonyl or 2,2,2-trichroloethoxycarbonyl);hydroxy(lower)alkoxycarbonyl such as 2-hydroxyethoxycarbonyl or 2(or3)-hydroxypropoxycarbonyl; lower alkoxy(lower)alkoxycarbonyl such as2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or 2(or 3)-methoxy(orethoxy)propoxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl,tolyloxycarbonyl, xylyloxycarbonyl or p-chlorophenoxycarbony;ar(lower)alkoxycarbonyl such as benzyloxycarbonyl,p-bromobenzyloxycarbonyl o-methoxybenzyloxycarbonyl orphenethyloxycarbonyl; ar(lower)alkoxy(lower)alkoxycarbonyl such as2-(benzyloxyl)ethoxycarbonyl or 2(or 3)-(benzyloxy)propoxycarbonyl;aryloxy(lower)alkoxycarbonyl such as 2-(phenoxy)ethoxycarbonyl or 2(or3)-(phenoxy)propoxycarbonyl; N- or N,N-(di)-substitutedamino(lower)alkoxycarbonyl such as N- orN,N-(di)-(lower)alkylamino(lower)alkoxycarbonyl (e.g. 1(or2)-[N-methyl(or N,N-dimethyl)amino]ethoxycarbonyl, 1(or 2)-[N-ethyl(orN,N-diethyl)amino]ethoxycarbonyl, or 1(or2)-(N-methyl-N-ethylamino)ethoxycarbonyl or N-loweralkyl-N-ar(lower)alkylamino(lower)alkoxycarbonyl(e.g.-2-(N-methyl-N-benzylamino)ethoxycarbonyl) and the like, andfurther R₂ and R₃ may be same or different;

Lower alkyl substituted with oxo includes lower alkanoyl such as formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyland lower alkanoyl(lower)alkyl such as formylmethyl, acetonyl,2-formylethyl, 3-formylpropyl or butyrylmethyl. The carbonyl groupthereof may be protected with suitable protecting group, and thusprotected carbonyl group in this invention means a group given byprotecting the carbonyl with conventionally employed protecting groupfor a carbonyl. Suitable examples of such protected carbonyl group areacetal, cyclic-acetal, thioacetal, cyclic-thioacetal,cyclic-monothioacetal or acylal types of group. Examples of these loweralkyl containing such protected carbonyl group aregem-di(lower)alkoxy(lower)alkyl (e.g. dimethoxymethyl,1,1-dimethoxyethyl, diethoxymethyl, dipropoxymethyl, 2,2-diethoxyethylor 2,2-diethoxypropyl); gem-lower alkylenedioxy(lower)alkyl (e.g.1,3-dioxolan-2-yl, 2-methyl-1,3-dioxolan-2-yl,4-methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,3-dioxolan-2-yl,1,3-dioxan-2-yl, 2-methyl-1,3-dioxan-2-yl, 1,3-dioxolan-2-ylmethyl,2-methyl-1,3-dioxolan-2-ylmethyl or 3-(1,3-dioxolan-2-yl)propyl);gem-di(lower)alkylthio(lower)-alkyl (e.g. dimethylthiomethyl,1,1-dimethylthioethyl, diethylthiomethyl or 2,2-diethylthioethyl);gem-lower alkylenedithio(lower)alkyl (e.g. 1,3-dithiolan-2-yl,2-methyl-1,3-dithiolan-2 -yl, 4-methyl-1,3-dithiolan-2-yl,4,5-dimethyl-1,3-dithiolan-2-yl, 1,3-dithian-2-yl,2-methyl-1,3-dithian-2-yl, 1,3-dithiolan-2-ylmethyl,2-methyl-1,3-dithiolan-2-ylmethyl or 3-(1,3-dithiolan-2-yl)propyl); andgem-di(lower)alkanoyloxy(lower)alkyl (e.g. diacetoxymethyl,1,1-diacetoxyethyl, dipropionyloxymethyl, or 2,2-dipropionyloxyethyl); 5or 6-membered saturated 1-oxa-3-thioheterocyclic-1-yl(lower)alkyl (e.g.1,3-oxathiolan-2-yl, 2-methyl-1,3-oxathiolan-2-yl,4-methyl-1,3-oxathiolan-2-yl, 4,5-dimethyl-1,3-oxathiolan-2-yl,1,3-oxothian-2-yl, 2-methyl-1,3-oxothian-2-yl,1,3-oxathiolan-2-ylmethyl, 2-methyl-1,3-oxathiolan-2-ylmethyl or3-(1,3-oxathiolan-2-yl)propyl).

A 5 or 6-membered saturated N-contianing heterocyclic-1-yl group may beone which may contain additional one or more hetero atom(s) selectedfrom nitrogen, sulfur and oxygen atoms such as pyrrolidin-1-yl,piperidino, imidazolidin-1-yl, morpholino or thiomorpholino, and it maybe optionally substituted with hydroxy, lower alkyl orhydroxy(lower)alkyl such as hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl or 3-hydroxypropyl.

The other terms of each lower alkoxyimino, N'- orN',N'-di-(lower)alkylamino(lower)alkylimino, hydroxy(lower)alkylimino,N'- or N',N'-di-(lower)alkylamino(lower)alkylamino andhydroxy(lower)alkylamino will be clearly defined by applying optionallythe above given exemplifications of the terms to them.

According to the present invention, 1,4-dihydropyridine derivatives (I)can be produced by various processes, which fall into the followingclassification:

(I Construction of fundamental structure)

1. Ring formation of 1,4-dihydropyridine nucleus.

(II Transformations of functions)

2. Hydrolysis for removal of protecting group of protected carbonylgroup

3. Condensation to form imino-function.

4. Dehydration

5. Reduction of oxo- or imino-function.

6. Acylation of hydroxy-function.

7. Oxidation of alcohol to carbonyl compound.

8. Pyrolytic ring closure.

9. Other transformations.

Each of these processes will be hereinafter illustrated.

1. Ring formation of 1,4-dihydropyridine nucleus.

Some of the compound (I) representable by the following formula:##STR4## wherein R₁, R₂ and R₃ are each as defined above and R_(4a) andR_(5a) are each hydrogen, lower alkyl or lower alkyl substituted withoxo wherein thus formed carbonyl group is protected with suitableprotecting group, provided that at least one of R_(4a) and R_(5a) islower alkyl, substituted with oxo wherein thus formed carbonyl group isprotected with suitable protecting group, can be prepared by carryingout one of the reactions of the processes, which comprises

(1) reacting a compound of the formula: ##STR5## wherein R₁, R₃ andR_(5a) are each as defined above, with an amino compound of the formula:##STR6## wherein R₂ and R_(4a) are each as defined above,

(2) subjecting a mixture of an aldehyde compound of the formula:

    R.sub.1 --CHO                                              (II')

wherein R₁ is as defined above, an ester of β-ketonic acid of theformula:

    R.sub.5a --COCH.sub.2 --R.sub.3                            (II")

wherein R₃ and R_(5a) are each as defined above, and an amino compound(III) to reaction, or

(3) reacting an acetylene compound of the formula:

    R.sub.2 --C═C--R.sub.4a                                (III')

wherein R₂ and R_(4a) are each as defined above, with ammonia or anammonium salt and a compound (II).

The starting compound (II) used in the reactions (1) and (3) may benovel and prepared by reacting the aldehyde (II') with the β-ketoacidester (II") in a conventional manner, and the ammonium salt used in thereaction (3) includes an inorganic ammonium salt such as ammoniumchloride or ammonium sulfate, or an organic ammonium salt such asammonium acetate.

In the above reactions (1), (2) and (3), there can be employed thestarting compounds (II), (II"), (III) and (III') wherein the symbolsR_(4a) and R_(5a) are occasionally exchanged into each other, even whenboth symbols are not the same groups, and, in such case, thesubstantially same object compound (I-1) may be obtained not only whenR_(4a) and R_(5a) are the same groups, irrespective of R₂ and R₃ beingthe same groups or not, but also when R_(4a) and R_(5a) are not the samegroups and R₂ and R₃ are the same groups.

Regarding the reactions (1) and (2), the starting compound (II) mayinclude geometric isomers such as cis-trans isomers due to the doublebond in its molecule. Such cis-trans isomers may be equilibrated and,therefore, each or a mixture of the isomers of (II) may be applied asthe starting materials to provide the same object compound (I-1).

The reactions (1), (2) and (3) can be carried out at ambient temperatureor under warning or heating with or without a suitable solvent such asbenzene, toluene, xylene, chloroform, carbon tetrachloride, methylenechloride, ethylene chloride, methanol, propanol, butanol, water or otherconventional solvents. The reactions can be usually promoted in thepresence of an agent such as an acid (e.g. acetic acid), a base (e.g.pyridine or picoline) or in a conventional buffer solution. These agentsmay act as a reaction promotor and also used as a solvent when they arein liquid. The reactions can be also accelerated by heating. Thereaction condition may vary according to the kind of the reactants to beused.

2. Hydrolysis for removal of protecting group of protected carbonylgroup.

The compound of the formula: ##STR7## wherein R₁, R₂ and R₃ are each asdefined above and R_(4b) and R_(5b) are each hydrogen, lower alkyl orlower alkyl substituted with oxo, provided that at least one of R_(4b)and R_(5b) is lower alkyl substituted with oxo, can be prepared byhydrolyzing the compound (I-1) which can be obtained in theabove-mentioned ring formation process. In this process, the protectinggroup(s) of the carbonyl group on the alkyl group for R_(4a) and/orR_(5a) of the compound (I-1) is removed by hydrolysis.

Hydrolysis may be carried out in a conventional manner and, for example,the removal of the protecting groups of acetal-type and cyclicacetal-type is preferably carried out by an acidic hydrolysis, i.e. inthe presence of an acid such as an inorganic acid (e.g. hydrochloricacid or sulfuric acid) or an organic acid (e.g. formic acid, aceticacid, trifluoroacetic acid or p-toluenesulfonic acid); the removal ofthe protecting groups of thioacetal-type, cyclic thioacetal-type andcyclic monothioacetal type is preferably carried out by hydrolysis inthe presence of a heavy metal salt such as mercuric chloride or copperchloride; and the removal of the protecting group of acylal-type ispreferably carried out by the above mentioned acidic hydrolysis or abasic hydrolysis, i.e. in the presence of a base such as an inorganicbase (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate) or an organic base (e.g. sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide, pyridine orpicoline). These reactions of hydrolysis may be carried out in asuitable conventional solvent such as water, acetone, methyl ethylketone, dioxane, ethanol, methanol, N,N-dimethylformamide,N-methylmorpholine or dimethylsulfoxide, an optional mixture with wateror a buffer solution thereof. The reaction temperature is notrestrictive, and the reaction is usually conducted under cooling, atroom temperature or under somewhat elevated temperature.

3. Condensation to form imino function

The compound of the formula: ##STR8## wherein R₁, R₂ and R₃ are each asdefined above and R_(4c) and R_(5c) are each hydrogen, lower alkyl orsubstituted lower alkyl in which the subsituent is hydroxyimino,hydrazono, lower alkoxyimino, hydroxy(lower)alkylimino or N'- orN,N-di-(lower)alkylamino(lower)alkylimino, provided that at least one ofR_(4c) and R_(5c) is said substituted lower alkyl, may be prepared byreacting a compound of the formula: ##STR9## wherein R₁, R₂, R₃, R_(4b)and R_(5b) are each as defined above, with an amine of the formula:

    R.sub.8 --NH.sub.2                                         (IV)

wherein R₈ is hydroxy, amino, lower alkoxy, hydroxy(lower)alkyl or N- orN,N-di(lower)alkylamino(lower)alkyl.

According to this process the oxo group in R_(4b) and/or R_(5b) of thestarting compound (I-2) is replaced by the imino group of ═N--R₈(wherein R₈ is as defined above).

The starting compound (I-2) can be obtained by the above-mentionedhydrolysis process.

The reaction is carried out in a usual manner, for example, in thepresence of a catalyst, such as an acid (e.g. hydrochloric acid,hydrobromic acid, sulfuric acid, formic acid, acetic acid,p-toluenesulfornic acid, boron trifluoride, silicon tetrachloride ortitanium tetrachloride); in a basic condition realized by using the freeamino-compound (IV); or an acidic or basic conventional buffer solution,and usually in a suitable conventional solvent such as water, dioxane,ethanol, methanol or dimethylformamide or an optional mixture with waterthereof.

The reaction temperature is not restrictive, and the reaction is usuallycarried out under cooling, at room temperature or under somewhatelevated temperature. The amine (IV), which is used as a reactant,includes an N'- or N',N'-di-(lower)alkylamino(lower)alkylamine such asN'-methyl or N',N'-dimethylamino-ethylenediamine, N'-ethyl orN',N'-diethylethylenediamine, N'-ethyl orN',N'-dimethylaminotrimethylenediamine or N'-ethyl orN',N'-diethylaminotrimethylenediamine; hydroxy(lower)alkylamine such asethanolamine or propanolamine; hydroxylamine; hydrazine and loweralkoxyamine such as O-methyl-, O-ethyl-, O-propyl-, orO-isopropyl-hydroxyamine. And these amines may be used in the form ofsalt with an acid such as an inorganic acid (e.g. hydrochloric acid orsulfuric acid) or an organic acid (e.g. acetic acid).

4. Dehydration

The compound of the formula: ##STR10## wherein R₁, R₂ and R₃ are each asdefined above and R_(4d) and R_(5d) are each hydrogen, lower alkyl,cyano or ω-cyano(lower)alkyl, provided that, when one of R_(4d) andR_(5d) is hydrogen or lower alkyl, the other is always cyano orω-cyano(lower)alkyl, and when R_(4d) and R_(5d) are not hydrogen orlower alkyl, both of them are a group selected from cyano orω-cyano(lower)alkyl, or R_(4d) is hydrogen or lower alkyl and R₃ andR_(5d) are combined together to form a group of the formula: ##STR11##may be prepared by treating the compound of the formula: ##STR12##wherein R₁, R₂ and R₃ are each as defined above and R'_(4c) and R'_(5c)are each hydrogen, lower alkyl or ω-hydroxyimino(lower)alkyl, providedthat at least one of R'_(4c) and R'_(5c) is ω-hydroxyimino(lower)alkyl,with a dehydrating agent.

The starting compound (I-3') can be obtained by the above-mentionedcondensation process.

Suitable example of the dehydrating agent may be organic or inorganicconventional ones such as an acid (e.g. sulfuric acid, phosphoric acid,polyphosphoric acid, formic acid, acetic acid, ethane sulfonic acid orp-toluene sulfonic acid), an acid anhydride (e.g. acetic anhydride,benzoic anhydride or phthalic anhydride), an acid halide (e.g. acetylchloride, benzoyl chloride, trichloroacetylchloride, mesyl chloride,tosylchloride, ethyl chloroformate or phenylchloroformate), an inorganichalogen compound (e.g. thionylchloride, phosphorus pentachloride,phosphorus oxychloride, phosphorus tribromide, stannic chloride ortitanium tetrachloride), a carbodiimide (e.g.N,N'-dicyclohexylcarbodiimide orN-cyclohexyl-N'-morpholinoethylcarbodiimide), N,N'-carbonyldiimidazole,pentamethyleneketene-N-cyclohexylimine, ethoxyacetylene,2-ethyl-7-hydroxyisoxazolium salt, another phosphorus compound (e.g.phosphorus pentoxide, polyphosphoric acid ethylester, triethylphosphateor phenylphsphate) or the like. When an acid is used as the dehydratingagent, the reaction may be conveniently conducted in the presence of itsalkali metal salt (e.g. sodium salt or potassium salt), or the like.

This reaction is usually carried out in a conventional solvent such asdiethyl ether, dimethylformamide, pyridine, acetic acid, formic acid,benzene, carbon tetrachloride, chloroform, methylene chloride,tetrahydrofuran, dioxane, and the like, and usually carried out at roomtemperature or under heating, and the reaction temperature is notrestrictive to the above.

According to this process, the terminal --CH═N--OH function in R'_(4c)and/or R'_(5c) of the starting compound (I-3') is transformed into cyanofunction in the resultant compound (I-4), and further there tends toproduce the compound of the formula: ##STR13## wherein R₁ and R₂ areeach as defined above and R"_(4c) is hydrogen or lower alkyl when thestarting compound (I-3') wherein R'_(5c) is hydroxyiminomethyl istreated, for example, in rather highly acidic condition. The compound(I-4') and the process for preparation thereof are also included in thescope of this invention.

This dehydration process can be also carried out successively to theforegoing condensation process without any isolation of the compound(I-3'). This case is also included in the scope of this invention.

5. Reduction of oxo- or imino-function

The compound of the formula: ##STR14## wherein R₁, R₂ and R₃ are each asdefined above and R_(4e) and R_(5e) are each hydrogen, lower alkyl orsubstituted lower alkyl in which the substituent is hydroxy, Hydrazino,hydroxy(lower)-alkylamino or N'- orN',N'-di(lower)alkylamino(lower)alkylamino, provided that at least oneof R_(4e) and R_(5e) is said substituted lower alkyl or R_(4e) ishydrogen or lower alkyl and R₃ and R_(5e) are combined together to form##STR15## (wherein R₆ and R₇ are each as defined above), can be preparedby reducing the compound of the formula: ##STR16## wherein R₁, R₂ and R₃are each as defined above and R'_(4b) and R'_(5b) are each hydrogen,lower alkyl or substituted lower alkyl in which the substituent is oxo,hydrazono, hydroxy(lower)alkylimino or N'- orN',N'-di(lower)alkylamino(lower)alkylimino, provided that at least oneof R'_(4b) and R'_(5b) is said substituted lower alkyl.

The starting compound (I-2') can be prepared by either of theabove-mentioned process hydrolysis or condensation.

The reduction can be carried out by a conventional manner for reductionof oxo or imino to hydroxy or amino, respectively, for example,reduction with a reducing agent such as an alkali metal hydride (e.g.lithium borohydride, sodium borohydride, potassium borohydride or sodiumcyanoborohydride) or catalytic reduction for which catalyst may bepalladium carbon, palladium chloride or rhodium carbon and the like in asuitable conventional solvent. Examples of such solvents are water,methanol, ethanol, isopropanol, dimethylformamide, and the like. Thereaction temperature is not restrictive, and the reaction is usuallycarried out under cooling, at room temperature or at somewhat elevatedtemperature. And, the method of reduction may be optionally selectedaccording to the kind of the starting compound (I-2').

According to this process, each oxo- or imino-function in the startingcompound (I-2') is transformed into the hydroxy- or amino-function,respectively, in the resultant compound (I-5), and further, the compoundof the formula: ##STR17## wherein R₆ is as defined above and R_(4e) ishydrogen or lower alkyl, and the compound of the formula: ##STR18##wherein R₇ is as defined above and R_(4e) is hydrogen or lower alkyl,can be produced simultaneously via the compound (I-5) wherein R_(5e) ishydroxymethyl (when R₆ is hydrogen), 1-hydroxyethyl (when R₆ is methyl),2-(N',N'-diethylamino)ethylaminomethyl (when R₇ is2-(N,N-diethylamino)ethyl) or 2-hydroxyethylaminomethyl (when R₇ is2-hydroxyethyl), respectively.

These cases are also included in the scope of this invention.

6. Acylation of hydroxy function

The compound of the formula: ##STR19## wherein R₁, R₂ and R₃ are each asdefined above and R_(4f) and R_(5f) are each hydrogen, lower alkyl oracyloxy(lower)alkyl, provided that at least one of R_(4f) and R_(5f) isacyloxy(lower)alkyl, can be prepared by reacting the compound of theformula: ##STR20## wherein R₁, R₂ and R₃ are each as defined above andR'_(4e) and R'_(5e) are each hydrogen, lower alkyl orhydroxy(lower)alkyl, provided that at least one of R'_(4e) and R'_(5e)is hydroxy(lower)alkyl, with an acylating agent of the formula:

    R.sub.9 --OH                                               (V)

wherein R₉ is acyl, or its reactive derivative.

The starting compound (I-5') can be prepared in the above-mentionedreduction process.

Suitable examples of acyl for R₉ are lower alkanoyl which may besubstituted with carboxy, esterified carboxy, N- or N,N-di-substitutedamino or aryloxy, aroyl and the like.

Suitable acylating agent (V) includes lower alkanoic acid such as formicacid, acetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid or pivalic acid; carboxy(lower)alkanoicacid, i.e. di- or poly-basic carboxylic acid such as malonic acid,succinic acid, adipic acid, glutaric acid, pimeric acid or suberic acid;esterified carboxy(lower)alkanoic acid, i.e. a half ester of thepreceding di- or poly-basic carboxylic acid such as a respective halflower alkyl ester (e.g. methyl ester, ethyl ester or propyl ester); N-or N,N-di-substituted amino(lower)alkanoic acid such as N- orN,N-di-(lower)alkylamino(lower)alkanoic acid (e.g. N-methyl(orN,N-dimethylamino-acetic acid, 1(or 2)-[N-ethyl(orN,N-diethyl)amino]propionic acid or 1(or2)-[N-methyl-N-ethylamino]propionic acid) or N-loweralkyl-N-ar(lower)alkylamino(lower)alkanoic acid (e.g. 1-(or2)-[N-methyl-N-benzylamino]propionic acid; aryloxy(lower)alkanoic acidsuch as phenoxyacetic acid, tolyloxyacetic acid, 2(or 3 or4)-chlorophenoxyacetic acid, 2-[2(or 3 or 4)-chlorophenoxy]propionicacid, 2(or 3 or 4)-nitrophenoxyacetic acid or 2(or 3 or4)-methoxy-phenoxyacetic acid); and aromatic carboxylic acid such asbenzoic acid, naphthoic acid, toluic acid; and the like.

The reactive derivative at the carboxy group of the compound (V) may beits acid halide such as acid chloride; acid anhydride; active amide;azide; or reactive ester such as methyl ester, ethyl ester, cyanomethylester, p-nitrophenyl ester of pyranyl ester.

The reaction can be preferably carried out in the presence of a basesuch as an inorganic base (e.g. sodium hydroxide, potassium hydroxide,sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassiumcarbonate) or an organic base (e.g. N-methylpiperidine, triethylamine,pyridine, N-methylmorphorine or N,N-dimethylaniline), and a suitableconventional solvent such as pyridine, ether, dioxane, acetone,chloroform, methylene chloride, tetrahydrofuran, dimethylformamide,benzene or water. The reaction temperature is not restrictive, and thereaction is usually carried out under cooling, at room temperature orunder somewhat elevated temperature. If necessary, there may be used aconventional condensing agent such as phosphorus oxychloride,thionylchloride, N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morphorinoethylcarbodiimide,pentamethyleneketene-N-cyclohexylimine, alkoxyacetylene,2-ethyl-7-hydroxyisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)isoxazoliumhydroxide or 6-chloro-1-tosyloxybenzotriazole.

7. Oxidation of alcohol to aldehyde

The compound of the formula: ##STR21## wherein R₁, R₂ and R₃ are each asdefined above and R_(4g) and R_(5g) are each hydrogen, lower alkyl,formyl or ω-formyl(lower)alkyl, provided that, when one of R_(4g) andR_(5g) is hydrogen or lower alkyl, the other is always formyl orω-formyl(lower)alkyl, and R_(4g) and R_(5g) are not hydrogen or loweralkyl, both of them are a group selected from formyl andω-formyl(lower)alkyl, may be also prepared by oxidizing the compound ofthe formula ##STR22## wherein R₁, R₂ and R₃ are each as defined aboveand R"_(4e) and R"_(5e) are each hydrogen, lower alkyl, orω-hydroxy(lower)alkyl, provided that at least one of R"_(4e) and R"_(5e)is ω-hydroxy(lower)alkyl.

The starting compound (I-5") can be prepared in the above-mentionedreduction process.

The oxidation can be carried out by any conventional method whichselectively oxidize a primary alcohol function to the correspondingformyl function without any adverse influence on the other parts of thecompound (I-5").

A suitable oxidation is carried out by reacting the starting compound(I-5") with an organic sulfonic acid or its reactive derivative,preferably under warming and in the presence of a base, with or withouta solvent. This reaction may be proceeded via the organic sulfonic acidester of the compound (I-5") as an intermediate which may be produced inthe course of the reaction.

Suitable organic sulfonic acid may be methanesulfonic acid,p-toluenesulfonic acid, p-nitrophenylsulfonic acid and the like, and itsreactive derivative and the base can be referred to those of thecompound (V) as mentioned in the preceding acylation process.

8. Pyrolytic ring closure

The compound of the formula: ##STR23## wherein R₁ and R₂ are each asdefined above, R_(4h) is hydrogen or lower alkyl, and R₃ and R_(5h) arecombined together to form a group of the formula: ##STR24## in which R₆is as defined above, may be prepared by heating in neat or in aconventional solvent the compound (I-5) wherein R_(4e) is hydrogen orlower alkyl and R_(5e) is hydroxymethyl, or the compound (I-3) whereinR_(4c) is hydrogen or lower alkyl and R_(5c) is hydrazonomethyl,respectively.

A suitable conventional solvent includes water, methanol, ethanol,isopropanol, butanol, dioxane, benzene, toluene, dimethylformamide,tetrahydrofuran, or a conventional buffer solution and the like. Thereaction can be accelerated by the addition of a catalytic or moreamount of an organic or inorganic base such as trialkylamine (e.g.trimethylamine or triethylamine), pyridine, alkali metal compound (e.g.sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassiumbicarbonate) and the like, or an organic or inorganic acid such asacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid,boron trifluoride, silicon tetrachloride, titanium tetrachloride and thelike. The reaction temperature is not so much restrictive, and thereaction is preferably carried out under warming or heating.

9. Other transformations

(1) The compound (I) wherein R₁, R₂ and R₃ are as defined above and R₄and R₅ are each hydrogen, lower alkyl or lower alkyl substituted with a5 or 6-membered saturated N-containing heterocyclic-1-yl which may havehydroxy, lower alkyl or hydroxy(lower)alkyl, provided that at least oneof R₄ and R₅ is said substituted lower alkyl, can be prepared bysubjecting the compound (I-5') to halogenation of the hydroxy function,whereby a halo-compound is provided, followed by substitution reactionwith a 5 or 6-membered saturated imino-containing heterocyclic compound.

The first halogenation reaction can be carried out by reactinghalogenating agent such as conventional one (e.g. thionyl chloride,phosphorus tribromide, phosphorus pentachloride or phosgene) and otherone which comprises a combination of phosphorus compound such astriphenyl phosphine or tri(lower)alkyl phosphite (e.g. trimethylphosphite or triethyl phosphite) and a polyhalo(lower)alkane such ascarbon tetrachloride or carbon tetrabromide in a suitable solvent.Examples of the solvents may be carbon tetrachloride, chloroform,methylene chloride, benzene and the like. This reaction is preferablycarried out in around neutral conditions, therefore, the lattercombination agent is the most preferable one. On the contrary, in caseof the former conventional agent, it may be usually carried out onmaintaining neutrality of the reaction medium, for example, byneutralizing with a base or scavenging the resulting acidic substancesfrom the halogenating agent in the course of reaction performed. Thereaction temperature is usually varied in accordance with the kind ofhalogenating agent, and therefore, the reaction is preferably carriedout at somewhat elevated temperature (e.g. under warming or heating) incase of the latter combination agent, and at much more mildertemperature (e.g. under cooling or warming) in case of the formerconventional agent, and preferably under anhydrous conditions.

The second substitution reaction is carried out in a substantiallysimilar manner to that of aforementioned acylation process in thepresence or absence of a base. The reaction can be carried out in asuitable solvent such as chloroform, methylene chloride, benzene,acetone, ether, tetrahydrofuran, dimethylformamide, methanol, ethanol orpropanol. The reaction temperature is not restrictive, and the reactionis usually carried out at room temperature or at an elevated temperature(e.g. under warming or heating). According to this method, thehydroxy(lower)alkyl group for R'_(4e) and/or R'_(5e) of the compound(I-5') is transformed at first into the halo(lower)alkyl group and theninto the lower alkyl substituted with 5 or 6-membered saturatedN-containing heterocyclic group for R₄ and/or R₅ of the compound (I).

(2) The compound (I) wherein at least one of R₂ and R₃ is N- orN,N-di-substituted amino(lower)alkoxycarbonyl can be prepared byreacting the corresponding compound (I) wherein at least one of R₂ andR₃ is halo(lower)alkoxycarbonyl with a N- or N,N-di-substituted amine inaccordance with the substantially same manner as that of theabove-mentioned substitution reaction in (1).

(3) The compound (I) wherein at least one of R₂ and R₃ ishydroxy(lower)alkoxycarbonyl can be prepared by subjecting thecorresponding compound (I) wherein at least one of R₂ and R₃ ishalo(lower)alkoxycarbonyl to hydrolysis substantially in the same methodas that of the afore-mentioned hydrolysis process.

(4) The compound (I) wherein R₁, R₂ and R₃ are each as defined above andR₄ and R₅ are each hydrogen, lower alkyl or substituted lower alkylselected from gem-di-(lower)alkoxy(lower)alkyl; gem-loweralkylenedioxy(lower)alkyl; gem-di-(lower)alkylthio(lower)alkyl andgem-(lower)alkylene-dithio(lower)alkyl, provided that at least one of R₄and R₅ is said substituted lower alkyl can be also prepared by reactingthe corresponding compount (I-2) with a hydroxy compound such as loweralkanol (e.g. methanol, ethanol or propanol) or lower alkane diol (e.g.ethylene glycol, propylene glycol, 2,3-butane diol or 1,3-propane diol);a thiol compound such as lower alkanethiol (e.g. methanethiol orethanethiol) or lower alkane dithiol (e.g. ethanedihiol,1,2-propanedithiol, 2,3-butanedithiol or 1,3-propanedithiol).

This reaction preferably carried out in the presence of catalytic amountof an organic or inorganic acid such as hydrochloric acid, sulfuricacid, acetic acid, boron trifluoride, zinc chloride or p-toluenesulfonicacid.

(5) The compund (I) wherein R₁, R₂ and R₃ are each as defined above andR₄ and R₅ are each hydrogen, lower alkyl or cyano(lower)alkyl, providedthat at least one of R₄ and R₅ is cyano(lower)alkyl can be prepared byreacting the halo-compound obtained in the above transformation (1) witha compound of the formula: R₁₀ --CN wherein R₁₀ is hydrogen or a metal.

Suitable metals for R₁₀ are alkali metal such as sodium or potassium,alkaline earth metal such as magnesium or calcium, heavy metal such asmercury or silver and the like.

The reaction is usually carried out at room temperature or under heatingin a suitable solvent such as water, methanol, ethanol, butanolchloroform, benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide,N-methylmorpholine, pyridine or other conventional solvent.

(6) In addition to the above, the compound of the formula: ##STR25##wherein

R₁, R₃, R₄ and R₅ are each as defined above, and

R₂ ' is hydroxy(lower)alkoxycarbonyl, may also be prepared by subjectinga compound of the formula: ##STR26## wherein

R₁, R₃, R₄ and R₅ are each as defined above, and

R₂ " is acyloxy(lower)alkoxycarbonyl, to hydrolysis in substantially thesame method as that of hydrolysis process.

A suitable acyloxy moiety in acyloxy(lower)alkoxycarbonyl includes loweralkanoyloxy such as formyloxy, acetoxy, propionyloxy and the like.

In accordance with the present invention, the product which is givenduring the reaction is separated and isolated from the reaction mixtureby methods commonly used for this purpose, and may be subjected toroutinely used purification procedures, for instance, torecrystallization from an appropriate solvent or a mixture of suchsolvents.

The compound (I) thus obtained wherein at least R₂ and R₃ or R₄ and R₅are not just same each other, includes stereoisomers due to the presenceof at least one asymmetric carbon atom at the fourth position of the1,4-dihydropyridine nucleus and can exist as each optical isomer or aracemic mixture. And further some of the compound (I) which has not lessthan two asymmetric carbon atoms in its molecule may exist as eachdiastereomer(s) or the mixture thereof. The mixture of the diastereomerscan be resolved into each racemic compound by conventional resolutionmethods such as chromatography or fractional recrystallization and thelike and the racemic compound can be resolved into each optical isomerby conventional method for racemic resolution such as a resolution byfractional recrystallization of a salt of the racemic compound with anoptically active acid, e.g., tartaric acid or camphor sulfonic acid.

The compound (I) is possessed of vasodilating activity and useful fortherapeutical treatment in hypertension and cardiovascular diseases suchas coronary insufficiency, angina pectoris or myocardial infarction.

The compositions of this invention comprise, as an active ingredient,the 1,4-dihydropyridine derivatives (I) in an amount of about 0.1 mg, toabout 500 mg., preferably about 1 mg. to about 50 mg. per daily oraldosage unit, with IV dosage being 10 to 25% of oral.

One skilled in the art will recognize that in determining the amounts ofthe active ingredient in the claimed dosage unit form, the activity ofthe ingredient as well as the size of the host animal must beconsidered. That is, on mg./kg. oral basis (see above ratio for IV), theamount of the active ingredient in the compositions will be about 1μg/kg. to about 10 mg./kg. and more, preferably about 0.5 mg./kg. toabout 5 mg./kg. For administration purpose of this pharmaceuticalcomposition, the active ingredients may be usually formed as tablet,granule, powder, capsule, suppository, suspensions, solutions and thelike. A pharmaceutical carrier or diluent includes solid or liquidnon-toxic pharmaceutically acceptable substances. Exemplar of solid orliquid carriers or diluents are lactose, magnesium stearate, terra albasucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia,peanut oil, olive oil or sesame oil, cacao butter or the like.Similarly, the carrier or diluent may include a time delay material suchas glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tabletted, placed in a hardgelatin capsule or in the form of a troche or lozenge.

The pharmacological activity of the 1,4-dihydropyridines of the formula(I) is demonstrated by standard procedures, that is, by administeringintravenously the following test 1,4-dihydropyridines to dogsanesthetized with pentobarbital and recording the coronary blood flow.The test results are given below: ##STR27##

Table. Increase of coronary blood flow (%)

The values indicate percentages compared to control [29.5±5.5 ml/min.].

    ______________________________________                                                 Dose μg/kg                                                        Compound    64           250    1000                                          ______________________________________                                        A          169           118    dead                                          B          190           174    155                                           C          214           168    175                                           D          171           195    179                                           E          185           215    144                                           F          173           159    156                                           G          199           195    170                                           H          182           205    174                                           ______________________________________                                    

Compound A is known as the generic name "Nifedipine" and alreadymarketed as a coronary vasodilator.

The following Examples are given merely for the purpose of illustratingthe syntheses of some specific object compounds of the presentinvention, but not of limiting the same thereto.

EXAMPLE 1

(1) A solution of 2-chlorobenzaldehyde (1.0543 g), ethyl4,4-diethoxyacetoacetate (1.6477 g) and piperidine (1 to 2 drop(s)) inbenzene (30 ml) was refluxed under azeotropic dehydration for 4.5 hours.After cooling, the resultant solution was washed with water and dried.The solvent was removed from the solution to give orange oil (2.7196 g)of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate. The mixtureof the compound obtained above and ethyl 3-amino-4,4-diethoxycrotonate(1.6580 g) was heated with stirring at about 100° C. for 1.5 hours andabout 120° C. for 8 hours. After cooling, the reaction mixture wasdissolved in ethyl acetate. The solution was washed with water anddried, and then the solvent was removed from the solution to give orangeoil (4.21 g) of diethyl2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.The product was purified by a column chromatography on silica gel withan eluent (benzene:ethyl acetate=10:1) to give pure product.

I.R. Spectrum (Film): ν(cm⁻¹): 3430, 1695, 1610, 1487, 1472, 1368, 1273,1200, 1093, 1059, 755.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.22 (18H, t, J=7 Hz), 3.3 to 3.9 (8H,m), 4.08 (4H, q, J=7 Hz), 5.55 (1H, s), 6.14 (2H, s), 6.9 to 7.5 (4H,m), 7.90 (1H, broad s).

(2)-(1) A solution of 2-chlorobenzaldehyde (14.0570 g), ethyl4,4-diethoxyacetoacetate (21.8240 g) and piperidine (1 ml) in benzene(100 ml) was refluxed under azeotropic dehydration for 4 hours. Theresultant solution was washed with water, dried and concentrated to giveoily ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate. The mixtureof the compound obtained above and ethyl 3-aminocrotonate (12.92 g) washeated in an oil bath (about 100° C.) for 8 hours. The reaction mixturewas dissolved in ethyl acetate, washed with water, dried and then thesolvent was removed to give crude oil (52.4 g). The oil was purified bycolumn chromatography on silica gel with an eluent (benzene:ethylacetate=20:1) to give diethyl2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,which was recrystallized from n-hexane to give the pure crystals(20.2445 g), m.p. 75° to 77° C.

(2)-(2) A solution of 2-chlorobenzaldehyde (1.4057 g), ethyl acetate(1.3014 g) and piperidine (5 drops) in benzene (10 ml) was refluxedunder azeotropic dehydration for 5 hours. After cooling, to theresultant solution was added benzene, and the solution was washed withwater twice and dried. The solvent was removed from the resultantsolution to give yellowish oil of ethyl2-(2-chlorobenzylidene)acetoacetate (2.7351 g). The mixture of thecompound obtained above and ethyl 3-amino-4,4-diethoxycrotonate (2.17 g)was heated at about 120° C. with stirring for 4 hours. After cooling,the resultant oil was dissolved in diethyl ether, washed with water andsaturated aqueous solution of sodium chloride in turn and then dried.The solution was concentrated under reduced pressure to give a reddishoil (4.5133 g). The product was purified by column chromatography onsilica gel with an eluent (benzene:ethyl acetate=20:1) to give yellowishoil of diethyl2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(2.25 g). The product was crystallized in n-hexane and the crystals werecollected by filtration, which were identified with the authenticsample.

(3) A mixture of 2-chlorobenzaldehyde (2.81 g), methyl4,4-dimethoxy-3-oxovalerate (3.81 g) and piperidine (0.2 ml) in benzene(20 ml) was refluxed under azeotropic dehydration for 7.5 hours. A smallamount of benzene was added to the reaction mixture and the resultantsolution was washed with water and dried over magnesium sulfate. Thesolvent was removed from the solution to give a reddish oil (7.04 g) ofmethyl 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxovalerate. The mixtureof the oily product (6.39 g) obtained above and methyl 3-aminocrotonate(2.33 g) was heated at 132° C. for 3.5 hours, allowed to stand and thendissolved in ethyl acetate. The resultant solution was washed with waterand an aqueous sodium chloride solution, and dried over magnesiumsulfate. The solvent was removed from the solution under reducedpressure to give a viscous and brown oil (8.28 g). This oil wassubjected to column chromatography on silica gel with an eluent (amixture of 20 parts of benzene and one part of ethyl acetate by volume)to give an oily substance (5.26 g).

This substance was dissolved in a mixture of ethyl acetate and diethylether and the solvent was removed under reduced pressure to givecolorless powder (1.0625 g). This powder was recrystallized from amixture of n-hexane and ethyl acetate to give faint yellow granules ofdimethyl2-methyl-4-(2-chlorophenyl)-6-α,1-dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 145° to 146° C.

(4)-(1) A solution of 2-nitrobenzaldehyde (9.0672 g), ethyl4,4-diethoxyacetoacetate (13.0944 g) and piperidine (1 ml) in benzene(45 ml) was refluxed under azeotropic dehydration for 3 hours. To theresultant solution was added water, and the solution was extracted withdiethyl ether. The extract was washed three times with water, dried andthen the solvent was removed under reduced pressure to give ethyl2-(2-nitrobenzylidene)-4, 4-diethoxyacetoacetate. The mixture of thecompound obtained above and ethyl 3-aminocrotonate (7.7496 g) was heatedin an oil bath (95° to 100° C.) for 8 hours. The resultant mixture wasextracted with diethyl ether, and the extract was washed with water anddried. The solvent was removed from the extract. The residue waspurified by column chromatography on silica gel with an eluent(benzene:ethyl acetate=20:1) to give oily diethyl2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(19.3 g). The product was crystallized in n-hexane and the crystals werecollected by filtration and then recrystallized from a mixture ofn-hexane and diethyl ether to give the pure compound, m.p. 80° to 81.5°C.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.16 (3H, t, J=7 Hz), 1.18 (3H, t, J=7Hz), 1.25 (6H, t, J=7 Hz), 2.37 (3H, s), 3.4 to 4.4 (8H, m), 5.92 (1H,s), 6.20 (1H,s), 6.67 (1H, broad s), 7.0 to 7.8 (4H, m).

(4)-(2) A solution of 2-nitrobenzaldehyde (3.0224 g), ethyl4,4-diethoxyacetoacetate (4.3650 g) and piperidine (240 mg) in benzene(12 ml) was refluxed under azeotropic dehydration for 80 minutes. Thereaction mixture was allowed to stand to cool, and ethyl acetate wasadded thereto. The mixture was washed with water twice and dried. Thesolvent was removed to give an orange-yellow oil (6.88 g). The oil waskept in a refrigerator overnight to give crystals. The crystals werecollected by filtration to give faint yellow crystals (3.3690 g), whichwere recrystallized from diisopropyl ether to give colorless granules(2.2479 g) of ethyl 2-(2-nitrobenzylidene)-4,4-diethoxyacetoacetate,m.p. 66° to 67.5° C. This product is one of the two isomers of ethyl2-(2-nitrobenzylidene)-4,4-diethoxyacetoacetate and shows signal at 5.23ppm(methine proton) and 8.31 ppm (olefinic proton) on N.M.R. spectrum(δ, CDCl₃). The filtrate was condensed and the resultant brown oil,which comprises the two isomers of ethyl2-(2-nitrobenzylidene)-4,4-diethoxyacetoacetate in the ratioapproximately 1:1 and shows signals of 4.93 and 5.23 ppm (methineproton) and 8.17 and 8.31 ppm (olefinic proton) on N.M.R. spectrum (δ,CDCl₃).

A mixture of the above obtained crystals (2.4497 g) and ethyl3-aminocrotonate (1.3508 g) was heated at 75° to 82° C. with stirringunder slightly reduced pressure for four hours and further heated at105° to 108° C. for five hours. The reaction mixture was cooled andcrystallized. The resultant crystals were recrystallized from a mixtureof diisopropyl ether and n-hexane to give crystals (0.5128 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylatewhich was identified with the product of the above Example 1-(4)-(1).

(5) A solution of 3-nitrobenzaldehyde (2.27 g), ethyl4,4-diethoxyacetoacetate (3.28 g) and piperidine (0.2 ml) in benzene (15ml) was refluxed under azeotropic dehydration for 3 hours. The resultantsolution was washed three times with water and dried over magnesiumsulfate. The solvent was removed from the reaction solution to give oilyethyl 2-(3-nitrobenzylidene)-4,4-diethoxyacetoacetate (6.0 g). Themixture of the compound obtained above and ethyl 3-aminocrotonate (1.94g) was heated at about 95° to 100° C. for 7 hours and then at about 120°C. for 1.5 hours with stirring. After cooling, the resultant oil wasextracted with ethyl acetate and the extract was washed with water anddried. The solvent was removed from the resultant solution to give anoil (7.8 g). The product was purified by column chromatography on silicagel with an eluent (benzene:ethyl acetate=20:1) to give the pure productof diethyl 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.65 g).

I.R. Spectrum (Film): ν(cm⁻¹): 3400, 1690, 1615, 1530, 1480, 1350, 1280,1200, 1090, 920, 765.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.23, 1.26 (12 H, t, t, J=7 Hz) 2.4(3H, s), 3.5 to 3.86 (4H, m), 4.11 (4H, q, J=7 Hz), 5.16 (1H, s), 6.82(1H, broad), 7.25 to 8.16 (4H, m).

(6) A mixture of ethyl2-(2-trifluoromethylbenzylidene)-4,4-diethoxyacetoacetate (7.48 g) andethyl 3-aminocrotonate (2.582 g) was heated at 130° C. for 5 hours. Theresultant mixture was dissolved in ethyl acetate and solution was washedwith water twice, dried over magnesium sulfate and concentrated underreduced pressure to give a red oil (9.8 g). The oil was subjected tocolumn chromatography on silica gel with an eluent (a mixture of 20parts of benzene and one part of diethyl ether by volume) to give anoily substance. This substance turned into crystals, which wererecrystallized from a mixture of n-hexane and diethyl ether to givecrystals of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 82° to 83° C.

(7) A solution of 2-methoxybenzaldehyde (2.7228 g), ethyl4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 or 5 drops) inbenzene (20 ml) was refluxed under azeotropic dehydration for 3 hours.The resultant solution was washed with water and dried. The solvent wasremoved from the extract to give oily ethyl2-(2-methoxybenzylidene)-4,4-diethoxyacetoacetate. The mixture of thecompound obtained above and ethyl 3-aminocrotonate (2.5832 g) was heatedin an oil bath (about 100° C.) for 7 hours. After cooling, the reactionmixture was extracted with diethyl ether, and the extract was washedwith water twice and dried over magnesium sulfate. The solvent wasremoved to give a red oil. The oil was purified by a columnchromatography on silica gel with an eluent (benzene:ethyl acetate=20:1)to give diethyl2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(5.0779 g). The product was recrystallized from n-hexane to give paleyellowish prisms, m.p. 105° to 107° C.

(8) A mixture of 2-chloro-5-nitrobenzaldehyde (3.73 g), ethyl4,4-diethoxyacetoacetate (4.365 g) and piperidine (272.5 mg) in benzene(10 ml) was refluxed under azeotropic dehydration for 1.5 hours. To themixture was added ethyl acetate, and the resultant mixture was washedthree times with water and then with an aqueous solution of sodiumchloride, and dried over magnesium sulfate. The solvent was removedunder reduced pressure to give a reddish brown oil (7.87 g) of ethyl2-(2-chloro-5-nitrobenzylidene)-4,4-diethoxyacetoacetate. The mixture ofthus obtained reddish brown oil and ethyl 3-aminocrotonate (3.48 g) washeated with stirring at 105° to 107° C. in an oil bath for 4.5 hours.The resultant mixture was extracted with ethyl acetate, and the extractwas washed with water three times and then with an aqueous solution ofsodium chloride, and dried over magnesium sulfate. After removal of thesolvent from the extract, the obtained residue (10.87 g) was subjectedto column chromatography on silica gel with an eluent (a mixture of 20parts of chloroform and one part of ethyl acetate by volume). Thefractions were checked with thin-layer chromatography and crystals (6.02g) were obtained by removing the solvent from the fraction containingthe designated substance. The crystals were recrystallized from amixture of diethyl ether and n-hexane to give crystals of diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 117° to 118° C.

(9) A solution of thiophene-2-carbaldehyde (2.2430 g), ethyl4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 drops) in benzene(20 ml) was refluxed under azeotropic dehydration for 4.5 hours. Aftercooling, to the resultant solution was added diethyl ether, and thesolution was washed with water and dried. The solvent was removed fromthe reaction mixture to give oily ethyl2-(2-thenylidene)-4,4-diethoxyacetoacetate. The mixture of the compoundobtained above and ethyl 3-aminocrotonate (2.6 g) was heated in an oilbath (about 100° C.) for 7.5 hours. The resultant mixture was dissolvedin diethyl ether, washed with water and dried. The solvent was removedto give brown oil (9.0 g). The oil was purified by column chromatographyon silica gel with an eluent (benzene:ethyl acetate=20:1) to givediethyl 2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. The product was recrystallized fromn-hexane to give yellowish crystals (2.2056 g), m.p. 77° to 77.5° C.

(10) To a mixture of 2-furaldehyde (2.88 g) and ethyl4,4-diethoxyacetoacetate (6.55 g) in benzene (15 ml ) was added each onefourth portion of piperidine (408 mg) with an interval of 15 minutesunder refluxing with azeotropic dehydration. Thus obtained mixture wasrefluxed for another 30 minutes. To the reaction mixture was added ethylacetate, and the resultant mixture was washed with water three times andthen with an aqueous solution of sodium chloride and dried overmagnesium sulfate. The solvent was removed to give a reddish brown oil(9.47 g) of ethyl 2-(2-furfurylidene)-4,4-diethoxyacetoacetate. Then themixture of the oil gained above and ethyl 3-aminocrotonate (5.9 g) washeated at 105° C. under stirring for 7 hours. The resultant mixture wasextracted with ethyl acetate, and the extract was washed with water andan aqueous solution of sodium chloride and then dried over magnesiumsulfate. After removal of the solvent, the resultant oil was purified bycolumn chromatography on silica-gel with an eluent (a mixture of 20parts of chloroform and one part of ethyl acetate by volume) andcrystallized from n-hexane (3 ml). The obtained crystals were washedwith n-hexane to result crystals (7.05 g). The resultant crystals (500mg) were recrystallized from n-hexane to give crystals (450 mg) ofdiethyl2-methyl-4-(2-furyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 59° to 60° C.

(11) A mixture of 2-nitrobenzaldehyde (3.02 g), 2-ethoxyethylacetoacetate (3.48 g) and piperidine (272.5 mg) in benzene (10 ml) wasrefluxed under azeotropic dehydration for 1.5 hours. The mixture waswashed with water three times and with an aqueous solution of sodiumchloride, dried over magnesium sulfate and concentrated. To theresultant oil of 2-ethoxyethyl 2-(2-nitrobenzylidene)acetoacetate wasadded ethyl 3-amino-4,4-diethoxycrotonate (4.77 g) and the mixture washeated at 110° C. under stirring for 5 hours. The reaction mixture wasextracted with ethyl acetate and the extract was washed with water threetimes and dried over magnesium sulfate. After removal of the solvent,the resultant brown oil was purified by column chromatography with aneluent (a mixture of ten parts of benzene and one part of ethyl acetateby volume) to give an oil (3.18 g) of 2-ethoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3420, 1730, 1695, 1650, 1610, 1530, 1480,1355, 1275, 1210, 1100, 860, 830, 785, 752, 715.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1 to 1.37 (12H, m), 2.37 (3H, s), 3.28to 4.3 (12H, m), 5.93 (1H, s), 6.2 (1H, s), 6.78 (1H, m), 7.23 to 7.83(4H, m).

(12) A mixture of 2-nitrobenzaldehyde (4.536 g), 2-chloroethylacetoacetate (4.94 g) and piperidine (110 mg) in benzene (18 ml) andacetic acid (360 mg) was refluxed for an hour under azeotropicdehydration. The reaction mixture was washed with water and dried. Thesolvent was distilled off to give an reddish oil of B 2-chloroethyl2-(2-nitrobenzylidene)acetoacetate, and thus obtained oil was treatedwith ethyl 3-amino-4,4-diethoxycrotonate (7.1 g) to give yellow granulesof 2-chloroethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 82° to 84° C. (recrystallized from diisopropyl ether).

(13) A mixture of 2-nitrobenzaldehyde (3.023 g), benzyl acetoacetate(3.802 g) and piperidine (272.5 mg) in benzene (10 ml), was treated in asubstantially similar manner that of Example 1-(11) to give a brown oil(6.94 g) of benzyl 2-(2-nitrobenzylidene)acetoacetate, which was furthertreated with ethyl 3-amino-4,4-diethoxycrotonate (4.34 g) to give a darkbrown oil (10.3 g). This oil was purified by column chromatography onsilica-gel and the resultant oil (3.8 g) was crystallized to givecrystals (1.65 g) of benzyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 103° to 103.5° C. (recrystallized from a mixture of diisopropylether and n-hexane).

(14) In an essentially similar manner to that of Example 1-(11) given inthe above, the following compounds were obtained:

Starting from a mixture of 2-nitrobenzaldehyde (3.02 g),2-benzyloxyethyl acetoacetate (4.72 g), piperidine (272.5 mg) in benzene(10.8 ml) was obtained 2-benzyloxyethyl2-(2-nitrobenzylidene)acetoacetate, which was further treated with ethyl3-amino-4,4-diethoxycrotonate to give an oil (4.80 g) of2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3400, 1700, 1650, 1610, 1530, 1480 1355,1273, 1205, 1090, 1055, 750, 700.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.1 to 1.3 (9H, m), 2.32 (3H, s), 3.45to 4.32 (10H, m), 4.46 (2H, s), 5.94 (1H, s), 6.2 (1H, s), 6.82 (1H, s),7.16 to 7.74 (9H, m).

(15) In an essentially similar manner to that of Example 1-(11) given inthe above, the following compounds were obtained:

Starting from a mixture of 2-nitrobenzaldehyde (3.02 g), 2-phenoxyethylacetoacetate (4.44 g), piperidine (272.5 mg) in benzene (10.8 ml) wasobtained an oil (8.0 g) of 2-phenoxyethyl2-(2-nitrobenzylidene)acetoacetate. Thus obtained oil was treated withethyl 3-amino-4,4-diethoxycrotonate (4.34 g) to give an oil of2-phenoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3410, 1700, 1602, 1535, 1480, 1356, 1277,1250, 1210, 1100, 1060, 755, 695.

N.M.R. Spectrum (δ, CDCl₃) ppm: 1.13 (3H, t, J=7 Hz), 1.23 (6H, t, J=7Hz) 2.33 (3H, s), 3.41 to 4.47 (10H, m), 5.91 (1H, s), 6.17 (1H, s),6.71 to 7.71 (9H, m).

(16) A mixture of 3-nitrobenzaldehyde (4.54 g), 2-ethoxyethylacetoacetate (5.23 g) and piperidine (85.2 mg) in benzene (15 ml) wasrefluxed under azeotropic dehydration for 3 hours. The resultant mixturewas washed with water, an aqueous solution saturated with sodiumchloride and water in turn, dried and concentrated to give an oil of2-ethoxyethyl 2-(3-nitriobenzylidene)acetoacetate. To this oily productwas added ethyl 3-amino-4,4-diethoxycrotonate (6.5 g). The mixture washeated at 110° C. for about 3 hours. The reaction mixture was dissolvedin ethyl acetate and washed with water twice and dried. The solvent wasremoved from the mixture to give an oil (15.58 g). This oil wassubjected to column chromatography on silica gel with an eluent (amixture of 10 parts of benzene and one part of ethyl acetate by volume)to give an oily substance (8.09 g). This oily substance (0.93 g) wastreated with a mixture of n-hexane and diethyl ether to give crystals,which were further recrystallized from a mixture of n-hexane and diethylether to give yellow granules (565.2 mg) of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 99° to 100° C.

(17) A mixture of 2-chloroethyl 2-(3-nitrobenzylidene)acetoacetate (16g) and ethyl 3-amino-4,4-diethoxycrotonate (10.85 g) was heated at 100°C. for 3 hours and allowed to stand overnight at room temperature.Appearing crystals were collected by filtration to give yellow crystals(7.02 g), and then the filtrate was subjected to column chromatographyon silica gel with an eluent [a mixture of 20 parts of benzene and onepart of ethyl acetate by volume] to give an oil (7.4 g). The oil wasallowed to stand to give crystals (3.6 g) and put together with theabove obtained crystals (7.02 g). These crystals were recrystallizedfrom a mixture of n-hexane and diethyl ether to give 2-chloroethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 96° to 97° C.

(18) A mixture of ethyl 2-(3-hyroxybenzylidene)acetoacetate (2.1 g) andethyl 3-amino-4,4-diethoxycrotonate (1.95 g) in n-propyl alcohol (1.5ml) was heated at 105° C. for 4.5 hours. After removal of the solventfrom the reaction mixture under reduced pressure, ethyl acetate wasadded to the residue. The resultant solution was washed with water twiceand an aqueous sodium chloride solution in turn, and then dried overmagnesium sulfate. The solvent was removed from the solution to give redoil (4.2 g). The oil was subjected to column chromatography on silicagel with an eluent [a mixture of 10 parts of benzene and one part ofdiethyl ether by volume] to give an oily substance, which wascrystallized from n-hexane to give crystals (1.5 g), These crystals (280mg) were recrystallized from a mixture of n-hexane and diethyl ether togive crystals of diethyl2-methyl-4-(3-hydroxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(106.2 mg), m.p. 107° to 108° C.

(19) A solution of 2-chlorobenzaldehyde (351.4 mg), ethyl4,4-diethoxyacetoacetate (545.6 mg) and ethyl 3-aminocrotonate (322.9mg) in n-propanol (2 ml) was refluxed for 10 hours. The resultantsolution was concentrated, and the residue was dissolved in ether, andthen washed twice with water. After drying the extract over magnesiumsulfate, the solvent was removed from the extract to give orange oil(1.1765 g). The oil was purified by a column chromatography on silicagel with an eluent (benzene:ethyl acetate=20:1) to give oily diethyl2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(374.6 mg). The product was dissolved in n-hexane and allowed to standin a refrigerator, and the precipitated crystals were collected byfiltration and washed with n-hexane to give pure crystals, m.p. 75° to77° C.

(20) A mixture of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate(2.42 g), ammonium acetate (1 g) and methyl propiolate (1 ml) in aceticacid (1 ml) was refluxed for 30 minutes. The reaction mixture was pouredinto an aqueous solution of sodium bicarbonate and extracted twice withethyl acetate. The ethyl acetate layer was washed with water and thenwith a saturated aqueous solution of sodium chloride, dried, and furtherconcentrated. The resultant red oil was dissolved in diethyl ether andappeared crystals were filtered off. The filtrate was concentrated togive a brown oil (2.57 g). This oil was purified by colomnchromatography on silica-gel with an eluent (a mixture of ten parts ofbenzene and one part of ethyl acetate by volume). The fractioncontaining the designated substance was concentrated to give a yellowoil (1.03 g) of methyl4-(2-chlorophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3350, 1700, 1590, 760.

N.M.R. Spectrum (δ, CDCl₃): ppm: 5.45 (1H, s), 6.20 (1H, s).

(21) Similarly, the following compounds were obtained:

(1) 2-(N-Benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3400, 1700, 1690, 1610, 1523, 1475, 1350,1275, 1197, 1092, 1055, 755, 698.

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.21 (9H, t, J=7 Hz), 2.21 (3H,s), 2.36 (3H, s), 2.63 (2H, t, J=6 Hz), 3.5 (2H, s), 3.65 (2H, q, J=7Hz), 3.66 (2H, q, J=7 Hz), 4.1 (2H, q), 4.18 (2H, t, J=6 Hz), 5.18 (1H,s), 6.2 (1H, s), 6.86 (1H, s), 7.16 to 8.16 (4H, m).

(2) 2-(N,N-Diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(a brown oil).

(3) 2-Hydroxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 98° to 100° C.

(4) 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,-4-dihydropyridine-3-carboxylate.

I.R. Spectrutm (film): ν(cm⁻¹): 3530, 3410, 3360 (shoulder), 1706(shoulder), 1697, 1690 (shoulder), 1532, 1480, 1356, 1275, 1208, 1100,1105, 860, 832, 785.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.0 to 1.45 (9H, m), 2.39 (3H, s), 2.2to 2.73 (1H, broad), 3.4 to 4.5 (10H, m).

(5) Diethyl2-methyl-4-(2-nitrophenyl)-6-ethylenedioxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 152° to 153.5° C.

EXAMPLE 2

(1) To a solution of diethyl2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(1.7 g) in acetone (17 ml) was added 6N-hydrochloric acid (1.5 ml) andstirred at room temperature for 3 hours. After removing the solvent, theresidue was extracted with diethyl ether and the extract was washed withwater and dried. The solvent was removed from the extract to givediethyl2,6-diformyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(1.35 g). The product was recrystallized from diethyl ether to give pureyellowish granules, m.p. 85° to 86° C.

(2) To a solution of diethyl2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(452 mg) in acetone (5 ml) was added 6N-hydrochloric acid (0.2 to 0.3ml) and stirred at room temperature for an hour. After removing acetone,the residue was extracted with ethyl acetate twice and the extract waswashed with water and dried. The solvent was removed from the extract togive diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate.The product was recrystallized from a mixture of n-hexane and diethylether to give the pure product, m.p. 87° to 88° C.

(3) To a solution of dimethyl2-methyl-4-(2-chlorophenyl)-6-(1,1-dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarboxylate(409.9 mg) in acetone (5 ml) was added 6N hydrochloric acid (0.5 ml) andstirred at room temperature for 17 minutes. The reaction mixture wasneutralized with an aqueous solution saturated with sodium bicarbonateand the solvent was distilled off under reduced pressure. Water wasadded to the residue and the mixture was allowed to stand to givecrystals, which were collected by filtration and dried to give crystals(350.2 mg). These crystals were recrystallized from a mixture ofn-hexane and ethyl acetate to give yellow granules of dimethyl2-methyl-4-(2-chlorophenyl)-6-acetyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 161° to 162° C.

(4) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1563 g) in acetone (10 ml) was added 6N-hydrochloric acid (2.5 ml)and stirred at room temperature for 30 minutes. After removing acetone,water was added to the residue and neutralized with aqueous solution ofsodium bicarbonate. The precipitated solid was collected by filtration,washed with water and then dried to give yellowish powder of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(0.9407 g). The product was recrystallized from a mixture of ethanol andn-hexane to give the pure product, m.p. 101° to 103° C.

(5) To a solution of diethyl2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(462.5 mg) in acetone (4 ml) was added 6N-hydrochloric acid (0.4 ml) andstirred at room temperature for an hour. After the reaction, the solventwas removed from the resultant solution. To the residue was added water,and the residue was pulverized. The powder was collected by filtration,washed with water and dried to give diethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(360 mg), m.p. 130° to 133° C.

(6) To a solution of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(5.2 g) in acetone (5 ml) was added 6N-hydrochloric acid (5 ml) andstirred at room temperature for about 1.5 hours. After removal of theacetone, water was added to the residue and the resultant aqueoussolution was extracted with ethyl acetate twice. The extract was washedwith water and dried and the solvent was removed therefrom to give areddish oil (4.2 g) of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (Nujol): ν(cm⁻¹): 3350, 1700, 1640, 1605, 1480, 1370,1308, 1200, 1100, 1035, 950, 763

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.2 (6H, t, J=7 Hz), 2.4 (3H, s),3.92 to 4.38 (4H, m), 5.72 (1H, s), 7.06 (1H, s), 7.24 to 7.62 (4H, m).

(7) To a solution of diethyl2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(447.5 mg) in acetone (7.5 ml) was added 6N-hydrochloric acid (0.2 ml)and stirred at room temperature for an hour. The resultant mixture wastreated in a similar manner to Example 2-(4), to give reddish yellowcrystals of diethyl2-methyl-4-(2-methoxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(373.2 mg). The product was recrystallized from a mixture of diethylether and n-hexane to give the pure product, m.p. 111° to 112° C.

(8) To a solution of diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(5.45 g) in acetone (54.5 ml) was added 6N hydrochloric acid (5 ml) andthe resultant mixture was stirred at room temperature for 1.5 hours.After removal of the acetone from the reaction mixture, water was addedto the residue and the mixture was allowed to stand for 15 minutes. Theprecipitated crystals were collected by filtration, washed with waterand dried to give crystals (4.2 g). Thus obtained crystals (500 mg) wererecrystallized from a mixture of n-hexane and ethyl acetate to givecrystals (347 mg) of diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 172° to 173° C.

(9) To a solution of diethyl2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(424 mg) in acetone (15 ml) was added 6N-hydrochloric acid (0.2 ml) andthis solution was stirred at room temperature for an hour. The resultantsolution was concentrated and the residue was extracted with diethylether. The extract was washed with water and dried and then the solventwas removed to give yellowish oil of diethyl2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,which was soon crystallized. The product was recrystallized from amixture of n-hexane and diethyl ether to give the pure product (247.7mg), m.p. 67° to 68.5° C.

(10) To a solution of diethyl2-methyl-4-(2-furyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(6.6 g) in acetone (66 ml) was added 6N hydrochloric acid (6.6 ml) andthe resultant mixture was stirred for one and three-fourth hour at roomtemperature. After removal of the acetone from the reaction mixture, theresidue was extracted with ethyl acetate. The extract was washed withwater, dried and concentrated. The resultant oil (6.1 g) was subjectedto column chromatography on silica-gel with an eluent (a mixture of 20parts of chloroform and one part of ethyl acetate by volume). Theconcentrate (oil, 2.4 g) of the fraction of the eluate which showed onespot on thin-layer chromatography gave crystals (1.79 g) and theconcentrate (700 mg) of the fraction of the eluent which showed pluralspots on thin-layer chromatography gave crystals (410 mg). Thesecrystals were combined together and recrystallized from n-hexane to giveneedles (400 mg) of diethyl2-methyl-4-(2-furyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 78° to 79.5° C.

(11) Starting from a mixture of 2-ethoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(1.9 g) in acetone (19 ml) and 6N hydrochloric acid (1.9 ml), wasobtained, by applying an essentially similar manner to that of Example2-(1), crystals of 2-ethoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,m.p. 107° to 108° C. (recrystallized from diisopropyl ether).

(12) To a solution of 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(2.5 g) in acetone (30 ml) was added 6N hydrochloric acid (1 ml) andtreated in a substantially similar manner to those of Example 2-(6) togive a viscous oil (2.10 g) of 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.

N.M.R. Spectrum (δ, CDCl₃): ppm: 6.07 (1H, s), 10.43 (1H, s).

(13) In a substantially similar manner to that of Example 2-(6), wastreated a mixture of benzyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(1.5 g) in acetone (15 ml) and 6N hydrochloric acid (1.5 ml) to give areddish brown oil which was crystallized and washed with n-hexane togive crystals (1.30 g) of benzyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (Nujol): ν(cm⁻¹): 3400, 1699, 1673, 1608, 1530, 1490,1380, 1355, 1220, 1110, 1030, 835, 795.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.21 (3H, t, J=7 Hz), 2.38 (3H, s), 4to 4.4 (2H, m), 5.07 (2H, s), 6.01 (1H, s), 6.9 (1H, broad s), 7.25 to7.8 (9H, m), 10.33 (1H, s).

(14) Starting from a mixture of an oil (2.5 g) of 2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylatein acetone (25 ml) and 6N hydrochloric acid (2 ml) was obtained areddish oil (2.05 g) of 2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,in a substantially similar manner to that of Example 2-(6).

I.R. Spectrum (film): ν(cm⁻¹): 3380, 1695, 1532, 1485, 1277, 1210, 1100,1040, 860, 750.

N.M.R. Spectrum (δ, CDCl₃): ppm: 2.40 (3H, s), 4.48 (2H, s), 6.08 (1H,s), 10.40 (1H, s).

(15) Starting from a mixture of 2-phenoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(1.24 g) in acetone (12 ml) and 6N hydrochloric acid (1.2 ml) wasobtained an oil (1.1 g) of 2-phenoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,in a substantially similar manner to that of Example 2-(6).

I.R. Spectrum (film): ν(cm⁻¹): 3400, 1700, 1640, 1600, 1530, 1480, 1350,1240, 1200, 1100, 860, 785 755, 692.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.2 (3H, t, J=7 Hz), 2.4 (3H, s), 3.98to 4.46 (6H, m), 6.03 (1H, s), 6.71 to 7.76 (9H, m), 10.4 (1H, s).

(16) To a solution of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(5.85 g) in acetone (60 ml) was added 6N hydrochloric acid (3 ml) andthe resultant mixture was stirred at room temperature for about 2 hours.The solvent was distilled off under reduced pressure and water added tothe residue. The mixture was extracted with ethyl acetate twice and theextract was washed with an aqueous sodium chloride solution and dried.The solvent was distilled off to give a reddish oil (5.7 g), which wasturned into crystals. These crystals were pulverized with a mixture ofn-hexane and diethyl ether and the resultant powder (4.81 g) wascollected by filtration. The powder (1.81 g) was recrystallized from amixture of diethyl ether and ethyl acetate to give orange-yellowgranules (1.2 g) of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,m.p. 100° to 101° C.

(17) To a solution of 2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(7.25 g) in acetone (70 ml) was added 6N-hydrochloric acid (7 ml) andthe resultant mixture was stirred at room temperature for 3 hours. Thesolvent was distilled off under reduced pressure. Water was added to theresidue, where an oily substance appeared. The aqueous mixture wasadjusted to an alkaline medium by addition of power of sodiumbicarbonate, and then extracted with ethyl acetate. The extract waswashed with water and dried, and the solvent was distilled off underreduced pressure to give a reddish oil (5.8 g) of2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.29 (3H, t, J=7 Hz), 2.21 (3H,s) 2.45 (3H, s), 2.63 (2H, t, J=6 Hz), 3.51 (2H, s), 3.95 to 4.42 (2H,t), 3.95 to 4.42 (2H, q), 5.28 (1H, s), 7.08 (1H, s), 7.28 to 8.12 (4H,m), 10.54 (1H, s).

I.R. Spectrum (Film): ν (cm⁻¹): 3350, 1735, 1700, 1690, 1635, 1600,1525, 1480, 1350, 1279, 1215, 1100, 1030, 735.

(18) To a mixture of a brown oil (2.46 g) of 2-(N,N-diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylatein acetone (24.6 ml) was added 6N hydrochloric acid (2.46 ml) and thismixture was stirred for two hours at room temperature. The reactionmixture was adjusted to pH 7 with an aqueous solution of sodiumbicarbonate and the acetone was distilled off. The residue was extractedwith ethyl acetate, and the extract was washed with water, dried, andconcentrated to give an oil (1.81 g) of 2-(N,N-diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.

N.M.R. Spectrum (δ, CDCl₃): ppm: 2.03 (3H, s), 5.3 (1H, s), 10.47 (1H,s).

(19) To a mixture of diethyl2-methyl-4-(3-hydroxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.16 g) in acetone (10 ml) was added 6N hydrochloric acid (1 ml) andthis mixture was stirred at room temperature for 1.5 hours. The solventwas distilled off under reduced pressure. The residue was added withwater and pulverized. The resultant suspension was extracted with ethylacetate and the extract was washed with water and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure and theresidue was treated with diethyl ether to give crystals (0.8 g). Thecrystals (200 mg) was recrystallized from a mixture of n-hexane anddiethyl ether to give pure crystals (130 mg) of diethyl2-methyl-4-(3-hydroxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 141.5° to 142.5° C.

(20) To a mixture of a yellow oil (360 mg) of methyl4-(2-chlorophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylatein acetone (10 ml) was added 6N hydrochloric acid (0.3 ml) and theresultant mixture was stirred for 1.5 hours at room temperature, and theacetone was removed. Water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried and concentrated. The resultant orange oil (0.26 g) wascrystallized and the crystals were washed with n-hexane to giveyellowish-orange powder (80.7 mg) of methyl4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (Nujol): ν (cm⁻¹): 3300, 1690, 1675, 1491, 1442, 1376,1303, 1221, 1186, 1090, 1060, 831, 757.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.0 (3H, t, J=7 Hz), 3.68 (3H, s), 4.18(2H, q, J=7 Hz), 5.56 (1H, s), 7 to 7.6 (6H, m), 10.44 (1H, s).

EXAMPLE 3

(1) The solution of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(377.8 mg), hydroxylamine hydrochloride (83.4 mg) and sodium carbonate(63.6 mg) in ethanol (1 ml) was stirred at room temperature for 30minutes. After concentrating the resultant solution, to the residue wasadded water. After the mixture was extracted with ethyl acetate, theextract was washed with water, and dried. The dried extract wasconcentrated to give yellowish oil (476 mg). The oil was crystallizedwith n-hexane to give diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate(318.8 mg), which was identified by converting to the corresponding6-cyano compound, m.p. 136° to 137° C.

(2) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(756 mg) in ethanol (2 ml) and 85% hydrazine hydrate (141 mg) in water(1 ml) was stirred at room temperature for an hour. The ethanol wasdistilled off under reduced pressure and the residue was extracted withethyl acetate. The extract was washed with water, dried over magnesiumsulfate and concentrated under reduced pressure to give an oil (960 mg).The oil was subjected to a column chromatography on silica gel with aneluent [a mixture of one part of benzene and one part of diethyl etherby volume] to give an oily substance (720 mg), which was allowed tostand for 14 days in a refrigerator to give needles (120 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-hydrazonomethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 107° to 110° C.

(3) To a mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(525.3 mg) and O-methylhydroxyamine hydrochloride (139.34 mg) in 99%ethanol (6 ml) was dropwise added a solution of sodium carbonate (88.5mg) in water (1 ml) over the period of 20 minutes under stirring at roomtemperature. The mixture was stirred for another 10 minutes. The ethanolwas distilled off under reduced pressure, and water was added to theresidue. The aqueous mixture was extracted with diethyl ether and theextract was washed with water twice and a saturated aqueous solution ofsodium chloride, dried and then concentrated under reduced pressure togive a yellow oil. The oil turned into crystals, and these crystals werewashed with n-hexane to give yellow powder (504.6 mg). This powder wasrecrystallized from a mixture of 10 parts of n-hexane and one part ofdiethyl ether by volume to give yellow glanules (301.5 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-methoxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 110° to 112° C.

(4) A mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1651 g), N,N-dimethyltrimethylenediamine (306.6 mg) andp-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) wasrefluxed under azeotropic dehydration for 4.5 hours. The resultantsolution was washed with water and dried. The solvent was removed fromthe solution to give brown oil (1.4748 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-[3-(N,N-dimethylamino)propyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (Film): ν (cm⁻¹): 3350, 1710, 1695, 1534, 1487, 1280,1200, 1100, 1043, 860, 828, 785, 753, 715, 680.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.18 (3H, t), 1.2 (3H, t), 2.25 (6H,s), 2.41 (3H, s), 3.67 (2H, broad t), 3.8 to 4.3 (8H, m), 5.97 (1H, s),7.2 to 7.8 (4H, m), 7.8 (1H, broad s), 8.97 (1H, t, J=1 Hz).

(5) A mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(970.9 mg), N,N-diethylethylenediamine (290.5 mg) and p-toluenesulfonicacid (catalytic amount) in dried benzene (20 ml) was refluxed underazeotropic dehydration for 4 hours. To the resultant solution was addeddiethyl ether and the solution was washed with water and dried. Thesolvent was removed to give red oil (1.1711 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (Film): ν (cm⁻¹): 3350, 1700, 1685, 1528, 1475, 1351,1273, 1090, 852, 821, 788, 746, 708.

N.M.R. Spectrum (δ, CDCl₃): ppm: 2.48 (3H, s), 5.99 (1H, s), 8.96 (1H,t, J=1 Hz).

(6) A mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1651 g), 2-aminoethanol (185 mg) and p-toluenesulfonic acid(catalytic amount) in dried benzene (20 ml) was refluxed underazeotropic dehydration for 1.5 hours. After cooling to room temperature,water was added to the resultant solution. The mixture was washed twicewith water. The aqueous layer was extracted with diethyl ether and theextract was combined with the benzene solution. The mixed solution wasdried over magnesium sulfate and then the solvent was removed from thesolution to give viscous oil (1.2397 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (Film): ν (cm⁻¹): 3500, 3360, 1694, 1536, 1484, 1280,1220, 1101, 762, 753.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.13 (3H, t, J=7 Hz), 1.20 (3H, t, J=7Hz), 2 (1H, broad s), 2.38 (3H, s), 3.8 to 4.3 (4H, m), 3.87 (4H, broads), 5.96 (1H, s), 7.2 to 7.8 (4H, m), 7.8 (1H, broad s), 9.0 (1H, broads).

(7)-(1) A mixture of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(870 mg), sodium carbonate (112.1 mg) and hydroxylamine hydrochloride(147 mg) in ethanol (5 ml) was stirred at room temperature for 30minutes. After removal of the ethaol, water was added to residue and thesolution was extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated under reduced pressure to give pasty oil (0.992g). The oil was purified by column chromatography on silica gel with aneluent [benzene (10)+ethyl acetate (1)] to give yellow powder (0.52 g)of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (Nujol): ν (cm⁻¹): 3410, 1695, 1680, 1655, 1483, 1445,1370, 1309, 1221, 1106, 1090, 1057, 1034, 1010, 985, 772.

N.M.R. Spectrum (δ: CDCl₃): ppm: 1.17 (3H, t, J=7 Hz), 1.20 (3H, t, J=7Hz), 2.35 (3H, s), 3.8 to 4.4 (4H, m), 5.64 (1H, broad s), 6.91 (1H,broad s), 7.2 to 7.7 (4H, m), 8.4 (1H, broad s), 8.8 (1H, s).

(7)-(2) To a solution of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.23 g) and hydroxylamine hydrochloride (250.2 mg) in ethanol (5 ml)was added a solution of sodium carbonate (190.0 mg) in water (1.5 ml).The mixture was stirred at room temperature for 30 minutes andconcentrated under reduced pressure. To the residue was added water andthe mixture was extracted with ethyl acetate. The extract was washedwith a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and concentrated under reduced pressure to give anoil. The oil was crystallized with n-hexane to give crude crystals (1.09g) of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

(8) To a mixture of 2-(N-methyl-N-benzylamino)ethyl 2-methyl4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.015 g) and hydroxylamine hydrochloride (116.8 mg) in ethanol (3 ml)was dropwise added slowly a solution of sodium carbonate (127.2 mg) inwater (1 ml) and the resultant mixture was stirred at room temperaturefor 50 minutes. The ethanol was distilled off under reduced pressure andto the residue was added water and the mixture was extracted with ethylacetate. The extract was washed with aqueous sodium chloride solution,dried and then concentrated under reduced pressure to give a yellow oil(1.01 g) of 2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν (cm⁻¹): 3350, 1690, 1460, 1375, 1348, 1205,1098, 1044, 738, 720, 700.

N.M.R. Spectrum (δ: CDCl₃): ppm: 1.22 (3H, t, J=7 Hz), 2.26 (3H, s),2.36 (3H, s), 2.70 (2H, t, J=6 Hz), 3.58 (2H, s), 4.09 (2H, q, J=7 Hz),4.18 (2H, t, J=6 Hz), 5.14 (1H, s), 7.1 to 8.1 (10H, m), 8.97 (1H, s).

(9) According to a similar manner to those of the above Example 3-(1) to-(8), the following compounds were obtained:

(1) Diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

(2) Diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

(3) Diethyl2-methyl-4-(2-furyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

(4) 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.

(5) 2-(N,N-Diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.

(6) Diethyl2-methyl-4-(3-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Those compounds were prepared from the corresponding 6-formyl compoundsin a similar manner to those of Examples 3-(1) to -(8) and wereidentified by converting them to the corresponding 6-cyano compounds

EXAMPLE 4

(1)-(1) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate(0.6135 g) and N,N'-dicyclohexylcarbodiimide (804.6 mg) in pyridine (3ml) was heated under reflux for 6 hours. The resultant solution wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The insoluble product was filtered off and the filtrate waswashed with water, dried over magnesium sulfate and evaporated underreduced pressure. To the residue was added diethyl ether and the mixturewas filtered. The filtrate was concentrated under reduced pressure togive red oil (703.7 mg). The oil was purified by column chromatographyon silica gel [eluent:benzene (10)+ethyl acetate (1)] and crystallizedwith n-hexane. The crystals were recrystallized from a mixture ofn-hexane and diethyl ether to give yellow crystals (417.1 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 136° to 137° C.

(1)-(2) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(377.8 mg), sodium formate (125 mg) and hydroxylamine hydrochloride(79.93 mg) in formic acid (1.5 ml) was heated under reflux for an hour.Water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The extract was filtered and the filtrate was washedwith water, an aqueous sodium bicarbonate solution, water and asaturated aqueous solution of sodium chloride in turn and dried overmagnesium sulfate. After the solvent was distilled from the solution,ether was added to the residue. The solution was filtered and thefiltrate was concentrated under reduced pressure to give oil (210 mg).The oil was crystallized from a mixture of n-hexane and diethyl ether togive crystals (154.1 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,which was identified with the authentic sample. The insoluble yellowpowder (110 mg) which was collected by filtration in the above was theproduct of ethyl 1-oxo-6-methyl-8-(2-chlorophenyl)-5,8-dihydro-1H-pyrido[2,3-d][1,2]oxazine-7-carboxylate.

I.R. Spectrum (Nujol): ν (cm⁻¹): 3340, 3250, 1730, 1693, 1686(shoulder), 1670, 1504, 1374, 1235, 1169, 1094, 972, 834, 778, 755

N.M.R. Spectrum (δ: DMSO-d₆): ppm: 0.98 (3H, t, J=7 Hz), 2.37 (3H, s),3.90 (2H, q, J=7 Hz), 5.35 (1H, s), 7.1 to 7.5 (4H, m), 10.02 (1H, s),10.35 (1H, s).

(1)-(3) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(377.8 mg), sodium formate (125 mg), hydroxylamine hydrochloride (79.93mg) in formic acid (1.5 ml) was stirred at room temperature for 5minutes and acetic anhydride (0.2 ml) was added to the solution. Themixture was stirred at room temperature for 20 minutes and heated underreflux for an hour. After adding water to the resultant solution, thesolution was extracted with ethyl acetate. The extract was washed withan aqueous sodium bicarbonate solution, water and a saturated aqueoussodium chloride solution in turn, dried over magnesium sulfate andconcentrated under reduced pressure to give brown oil (0.41 g). The oilwas crystallized from a mixture of diethyl ether and n-hexane to giveyellow powder (207 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,which was identified with the authentic sample.

(1)-(4) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(377.8 mg), sodium acetate (164 mg) and hydroxylamine hydrochloride (80mg) in acetic acid (1.5 ml) was stirred at room temperature for 30minutes. After acetic anhydride (0.2 ml) was added to the solution, thesolution was stirred at room temperature for an hour and then heatedunder reflux for an hour. Water was added to the reaction mixture, thesolution was extracted with diethyl ether. The extract was washed withwater, an aqueous sodium bicarbonate solution and water in turn anddried over magnesium sulfate. The solution was concentrated underreduced pressure to give yellow oil (410 mg). The oil was crystallizedwith n-hexane to give crystals (342.4 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,which was identified with the authentic sample.

(2) A mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.03 g), hydroxylamine hydrochloride (417 mg), sodium acetate (861.4mg) in acetic acid (15 ml) was stirred at room temperature for 30minutes. Acetic anhydride (1 ml) was added to the reaction mixture, andthe mixture was stirred at room temperature for 90 minutes and furtherrefluxed for an hour. The acetic acid was distilled off under reducedpressure, and to the resultant residue was added water, and the aqueousmixture was adjusted to pH 7 to 8 with sodium bicarbonate and extractedwith diethyl ether. The extract was washed with water, dried overmagnesium sulfate and then concentrated under reduced pressure to givean oil. This oil was subjected to column chromatography on silica gelwith an eluent [a mixture of 4 parts of benzene and one part of ethylacetate by volume]. The resultant oily substance (1.7 g) wascrystallized by treating with a mixture of diethyl ether and n-hexane.These crystals (1.5 g) were recrystallized from a mixture of diethylether and n-hexane to give pure crystals (1.23 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,mp 126° to 127.5° C.

(3)-(1) A solution of the powder (0.49 g) of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylateand thionyl chloride (1.5 ml) in dry diethyl ether (1.5 ml) was stirredat room temperature for 30 minutes. After the resultant solution wasevaporated to dryness, water was added to the residue and the mixturewas extracted with ethyl acetate. The extract was washed with water,dried over magnesium sulfate and concentrated under reduced pressure togive a brown oil (0.39 g). The oil was purified by a columnchromatography on silica gel with an eluent [benzene (5)+ethyl acetate(1)] and crystallized by treating with n-hexane to give yellow powder(50 mg). The powder was recrystallized from a mixture of diethyl etherand n-hexane to give crystals of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 140° to 143° C.

(3)-(2) A mixture of the crystals (1.09 g) of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylateand N,N'-dicyclohexylcarbodiimide (1.319 g) in pyridine (5 ml) washeated under reflux for 6.5 hours. After removing pyridine, dilutehydrochloric acid was added to the residue and the mixture was stirredfor 10 minutes. The mixture was extracted with ethyl acetate and theinsoluble product was filtered off. The filtrate was washed with water,dried over magnesium sulfate and concentrated under reduced pressure togive brown oil (1.09 g). The oil was purified by column chromatographyon silica gel with an eluent [benzene (10)+ethyl acetate (1)] to giveoil (720 mg). The oil was crystallized by treating with n-hexane and theprecipitates were collected by filtration and washed with n-hexane togive yellow powder (610 mg). The powder was recrystallized from amixture of ether and n-hexane to give pure diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,which was identified with the authentic sample, m.p. 140° to 143° C.

(3)-(3) A mixture of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(205.7 mg), sodium acetate (82 mg) and hydroxylamine hydrochloride (40mg) in acetic acid (1.5 ml) was stirred at room temperature for 30minutes. After acetic anhydride (0.1 ml) was added, the solution wasstirred at room temperature for 1.5 hours and then heated under refluxfor an hour. To the resultant solution was added water and the solutionwas extracted with diethyl ether. The extract was washed with water, anaqueous sodium bicarbonate solution and water in turn, dried overmagnesium sulfate and concentrated under reduced pressure to give oil(201 mg). The oil was purified by column chromatography on silica gelwith an eluent [benzene (5)+ethyl acetate (1)] to give pure oil (172.4mg). The oil was crystallized by treating with n-hexane to give powder(118 mg) of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate.

(4) A mixture of diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(3.70 g), hydroxylamine hydrochloride (695 mg), sodium acetate (1.436 g)in acetic acid (36 ml) was stirred at room temperature for 2.5 hours,and then acetic anhydride (2 ml) was added thereto. The resultantmixture was stirred for 30 minutes and refluxed for 1.5 hours. Afterremoval of the acetic acid, water and ethyl acetate were added to thereaction mixture and the resultant mixture was washed twice with dilutesodium bicarbonate aqueous solution and then with an aqueous sodiumchloride, and dried over magnesium sulfate. After removal of the solventthe residue was washed with diethyl ether to give powder (2.5 g). Thepowder was subjected to column chromatography on silica-gel with aneluent (a mixture of 10 parts of benzene and one part of ethyl acetateby volume). The fraction of the eluate which showed only one spot onthin-layer chromatography was concentrated to give crude crystals (450mg) and the fraction of the eluate which showed plural spots onthin-layer chromatography was also concentrated to give crude crystals(1.0 g). Thus obtained crude crystals were combined together andrecrystallized from a mixture of benzene and ethyl acetate to give purecrystals (657 mg) of diethyl2-methyl-4-(2-chloro-5-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 204.5° to 205.5° C.

(5) A mixture of diethyl2-methyl-4-(2-furyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.6g), hydroxylamine hydrochloride (383.6 mg) and sodium acetate (787.6 mg)in acetic acid (14 ml) was stirred for 30 minutes at room temperature.To the mixture, acetic anhydride (1 ml) was added and stirred for 1.5hours at room temperature and further stirred for an hour under reflux.After removal of the acetic acid from the reaction mixture, water wasadded to the residue and the mixture was extracted with ethyl acetate.The extract was washed with saturated sodium bicarbonate solution andwater and dried, and then the solvent was distilled off under reducedpressure. The resultant brown oil (1.8 g) was purified by columnchromatography on silica gel by an eluent (a mixture of 15 parts ofchloroform and one part of ethyl acetate by volume). The concentrate(920 mg) of the fraction of the eluate which showed one spot onthin-layer chromatography and the concentrate of one (450 mg) whichshowed plural spots respectively gave crystals (totally 875 mg) andthese were recrystallized from a mixture of diethyl ether and n-hexaneto give pure crystals (818 mg) of diethyl2-methyl-4-(2-furyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p.139° to 141° C.

(6)-(1) A mixture of 2-(N-benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate(0.91 g) and N,N'-dicyclohexylcarbodiimide (0.987 g) in pyridine (5 ml)was heated under reflux for 3 hours. After removal of the pyridine underreduced pressure, water was added to the residue. The mixture wasextracted with ethyl acetate. The insoluble product was filtered off andthe filtrate was washed with water, dried over magnesium sulfate andconcentrated under reduced pressure to give red oil (1.6 g). The oil waspurified by column chromatography on silica gel with an eluent [benzene(2)+ethyl acetate (1)] to give a reddish oil (0.68 g) of2-(N-benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (Nujol): ν (cm⁻¹): 3320, 3250 (shoulder), 2240, 1708,1685, 1525, 1500, 1345, 1293, 1210, 1100, 1030, 780, 735, 700.

N.M.R. Spectrum (δ: CDCl₃): ppm: 1.25 (3H, t, J=7 Hz), 2.15 (3H, s),2.39 (3H, s), 2.62 (2H, t, J=7 Hz), 3.48 (2H, s), 3.9 to 4.3 (4H, q (CH₂CH₃), t (COOCH₂ CH₂ N)), 5.26 (1H, s), 7.1 to 8.2 (10H, m).

The product obtained above was dissolved in diethyl ether. After addingethanolic hydrochloric acid to the solution, the solution was evaporatedto dryness. The residue was pulverized with n-hexane and theprecipitating powder was collected by filtration. The powder wasrecrystallized from an aqueous ethanol to give yellow pure crystals(460.8 mg) of the object compound hydrochloride, m.p. 228° to 229° C.

6-(2) A mixture of 2-(N-benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(253.8 mg), sodium acetate (82 mg) and hydroxylamine hydrochloride (40mg) in acetic acid (1 ml) was stirred at room temperature for 30minutes. After acetic anhydride (0.1 ml) was added, the solution wasstirred at room temperature for an hour and then heated under reflux foran hour. Water was added to the reaction mixture and the solution wasneutralized with sodium bicarbonate and then extracted with ethylacetate. The extract was washed with an aqueous sodium bicarbonatesolution and water in turn, dried over magnesium sulfate and thenconcentrated under reduced pressure to give an oil (250 mg)(quantitatively) of 2-(N-benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate,which was identified with the authentic sample.

(7) Starting from a mixture of an oil (1.66 g) of2-(N,N-diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,hydroxylamine hydrochloride (0.302 g) and sodium acetate (0.593 g) inacetic acid (12 ml) and acetic anhydride (1.8 ml) was obtained crystals(700 mg) according to a similar manner to that of Example 4-(2). Thesecrystals were recrystallized from ethanol to give pure crystals (420 mg)of 2-(N,N-diethylamino)ethyl2-methyl-4-(δ-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylte,m.p. 150° to 152° C.

(8) A mixture of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382g) in acetic acid (10 ml) was stirred for 30 minutes at roomtemperature. To this mixture was added acetic anhydride (1.4 ml) and theresultant mixture was stirred for an hour at room temperature andrefluxed or an hour. The acetic acid was distilled off under reducedpressure, and to the residue was added water. The resultant mixture wasneutralized with an aqueous solution of sodium bicarbonate and extractedwith ethyl acetate twice. The extract was washed with water and anaqueous solution saturated with sodium chloride and dried. The solventwas distilled off and thus obtained viscous oily substance (3.19 g) wassubjected to column chromatography on silica gel with an eluent [amixture of 5 parts of benzene and one part of ethyl acetate by volume]and a yellow oil (1.74 g) was obtained from the fraction which containedthe designated product. The oil turned into crystals (1.56 g). Thesecrystals were recrystallized from benzene to give yellow powder (1.5 g)of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.1/3benzene, m.p. 89° to 91° C. Thus obtained yellow powder was furtherrecrystallized from a mixture of diethyl ether and n-hexane to givecrystals of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate,m.p. 115° to 116° C.

(9) A mixture of diethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.9418 g), hydroxylamine hydrochloride (399.6 mg), sodium acetate (820mg) in acetic acid (7.5 ml) was stirred at room temperature for 30minutes. After addition of acetic anhydride (1 ml), the resultantmixture was stirred for an hour at room temperature and further refluxedfor an hour. The acetic acid was distilled off, and water was added tothe residue. The resultant aqueous mixture was neutralized by an aqueoussolution saturated with sodium bicarbonate. A precipitating oilysubstance was extracted with ethyl acetate twice. The extract was washedwith an aqueous solution of sodium chloride and dried. The solvent wasdistilled off under reduced pressure to give a orange-yellow oil (2.0103g). This oil turned into crystals and these crystals were recrystallizedfrom a mixture of diethyl ether, ethyl acetate and n-hexane to giveyellow powder (0.9119 g). This powder was dissolved into a mixture of 5parts of benzene and one part of ethyl acetate by volume and filtered onsilica gel to give crystals (1.02 g). These crystals were recrystallizedfrom a mixture of benzene and diethyl ether to give yellow granules(0.8479 g) of diethyl2-methyl-4-(3-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 174° to 177° C.

(10) Starting from a mixture of a reddish oil (2.0 g) of2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,hydroxylamine hydrochloride (336.9 mg), sodium acetate (662.9 mg) inacetic acid (15 ml) and acetic anhydride (1.5 ml) was obtained crystals(767 mg) according to a similar manner to that of Example 4-(2). Thesecrystals were recrystallized from a mixture of benzene and diethyl etherto give faint yellow crystals (450 mg) of 2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate,m.p. 139° to 140° C. (further recrystallized from a mixture of diethylether and n-hexane).

(11) Starting from a mixture of 2-phenoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.03 g), hydroxylamine hydrochloride (178.6 mg) and sodium acetate (352mg) in acetic acid (8 ml) and acetic anhydride (1 ml), there wasobtained in a similar manner to that of Example (4-2) an oil (420 mg) of2-phenoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (KBr): ν (cm⁻¹): 3330, 2250, 1710, 1600, 1530, 1500, 1300,1216, 1110, 757.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.2 (3H, t, J=7 Hz), 2.36 (3H, s), 4 to4.4 (6H, m), 6.05 (1H, s), 6.73 (1H, m), 6.83 to 7.66 (9H, m).

(12) Starting from a mixture of 2-ethoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(900 mg), hydroxylamine hydrochloride (167 mg) and sodium acetate (341mg) in acetic acid (7 ml) and acetic anhydride (1 ml) was obtained byapplying an essentially similar manner to that of Example 4-(2),crystals (420 mg) of 2-ethoxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate,m.p. 129° to 130.5° C. (recrystallized from a mixture of diethyl etherand n-hexane).

(13) Starting from a mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formylmethyl-1,4-dihydropyridine-3,5-dicarboxylate,hydroxylamine hydrochloride and sodium acetate in acetic acid and aceticanhydride, was obtained an oil of diethyl2-methyl-4-(2-nitrophenyl)-6-cyanomethyl-1,4-dihydropyridine-3,5-dicarboxylate,by applying an essentially similar manner to that of Example 4-(2).

I.R. Spectrum (Liquid): ν (cm⁻¹): 2210.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.17 (6H, t, J=7 Hz), 2.32 (3H, s), 3.9to 4.3 (4H, m), 4.78 (2H, s), 5.89 (1H, s), 7.14 (1H, broad s) 7.2 to7.85 (4H, m).

EXAMPLE 5

(1) To a solution of diethyl2,6-diformyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(272.7 mg) in 99% ethanol (7 ml) was added sodium borohydride (52.7 mg)under stirring at about 5° C. and the resultant mixture was furtherstirred at 5° C. for 10 minutes. The resultant solution was neutralizedwith dilute hydrochloric acid and ethanol was removed at roomtemperature under reduced pressure. To the residue was added water andthe precipitates were collected by filtration, and then dried to givecrude pale yellow crystals (261.0 mg) of diethyl2,6-dihydroxymethyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.The crude crystals were recrystallized from a mixture of ethanol anddiethyl ether to give pure pale yellow needles, m.p. 190° to 191° C.

(2) To a solution of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.5 g) in ethanol (30 ml) was added sodium borohydride (155 mg) understirring and this mixture was further stirred at room temperature for 2hours. The resultant mixture was acidified with dilute hydrochloric acidand the solvent was removed. Water was added to the residue and themixture was extracted twice with ethyl acetate. After the extract waswashed with water and dried, the solvent was removed under reducedpressure from the extract to give a red oil (1.3525 g). The oil wasdissolved in diethyl ether and allowed to stand at room temperature.After the insoluble product was removed by filtration, the filtrate wasallowed to stand. The slowly precipitated crystals were collected byfiltration and recrystallized from a mixture of diethyl ether andn-hexane to give pure crystals (92.0 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 143° C. The insoluble product obtained above was collected byfiltration and recrystallized from ethyl acetate to give colorlessprisms (241.5 mg) of ethyl2-methyl-4-(2-chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 211° to 212° C.

(3) To a mixture of dimethyl2-methyl-4-(2-chlorophenyl)-6-acetyl-1,4-dihydropyridine-3,5-dicarboxylate(450 mg) in methanol (15 ml) was added gradually sodium borohydride(46.8 mg) under ice-cooling with stirring. The mixture was furtherstirred for 35 minutes under ice-cooling. The solution was neutralizedwith 2N-hydrochloric acid under ice-cooling and the solvent wasdistilled off under reduced pressure at a lower temperature than 30° C.on a water-bath. To the residue was added water and a small amount of anaqueous sodium bicarbonate to adjust the medium to pH 7 to 8. Theresultant mixture was allowed to stand to give white powder, which wascollected by filtration and dried to give powder (395.0 mg). To thispowder was added diethyl ether (20 ml) and the mixture was stirred forabout 30 minutes at room temperature. Insoluble white powder wascollected by filtration and washed with diethyl ether. The filtrate andthe washings were combined together and the solvent was distilled off atrelatively low temperature to give crude crystals (100.5 g) of dimethyl2-methyl-4-(2-chlorophenyl)-6-(1-hydroxyethyl)-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 145° to 147° C.

The insoluble white powder obtained above was collected by filtrationand washed with diethyl ether to give crude white powder (264.2 mg) ofmethyl2-methyl-4-(2-chlorophenyl)-5-oxo-7-methyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 228° to 233° C.

(4) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.0881 g) in ethanol (20 ml) was gradually added sodium borohydride(0.1892 g) under stirring and the resultant mixture was further stirredat room temperature for an hour. The solution was acidified with dilutehydrochloric acid and stirred at room temperature for 30 minutes. Afterthe resultant solution was filtered, the filtrate was concentrated underreduced pressure and extracted with ethyl acetate. The extract waswashed with water and dried and then the solvent was removed to giveorange oil (1.8596 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate.After the crude product was dissolved in ethanol, the solution wasfiltered. The filtrate was concentrated under reduced pressure and theoily residue was allowed to stand for 3 days. Thus obtained crystalswere recrystallized from ether to give pure product, m.p. 112° to 113°C.

The insoluble product obtained by filtration of the resultant solutionin the above was recrystallized from ethanol to give pale yellow flakes(455.1 mg) of ethyl2-methyl-4-(2-nitrophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 220° to 222° C. The product was further recrystallized from ethylacetate to give pure product, m.p. 221° to 223° C.

(5) To a suspended solution of diethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(233 mg) in ethanol (10 ml) was added sodium borohydride (22.7 mg) at 0°to 5° C. under stirring and this mixture was further stirred at about 5°C. for an hour and 10 minutes. After the reaction, the mixture wasadjusted to pH 4 to 5 with 0.1N-hydrochloric acid, and then the solventwas removed under reduced pressure. The residue was extracted with ethylacetate and the extract was washed with water and dried over magnesiumsulfate. The extract was concentrated under reduced pressure and theresidue was crystallized by treating with a mixture of diethyl ether andn-hexane. The precipitated crystals were collected by filtration, driedand recrystallized from a mixture of diethyl ether and n-hexane to givecrystals of diethyl2-methyl-4-(3-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(152 mg), m.p. 141° to 142.5° C.

(6) To a solution of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.0 g) in ethanol (20 ml) was gradually added sodium borohydride (92mg) under stirring and ice-cooling and the resultant mixture was furtherstirred for 25 minutes. The resultant mixture was adjusted with 0.1Nhydrochloric acid to pH 4 to 5. The ethanol was removed under reducedpressure without heating so much, and water was added to the residue togive crystals. The crystals were collected by filtration to give crudecrystals (1.2 g). These were recrystallized from a mixture of diethylether and n-hexane to give pure crystals of diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 147° to 148.5° C.

(7) To a solution of diethyl2-methyl-4-(2-methoxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1320 g) in ethanol (30 ml) was gradually added sodium borohydride(114 mg) under stirring and the resultant mixture was further stirred atroom temperature for an hour. The resultant mixture was acidified withdilute hydrochloric acid. After removing ethanol from the mixture, waterwas added to the residue to solidify. The solid was collected byfiltration, dried and washed with diethyl ether. The diethyl etherwashings were concentrated to the volume of about 10 ml and stood atroom temperature to give pale yellowish granules (372.5 mg) of diethyl2-methyl-4-(2-methoxyphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 125° to 126° C.

On the other hand, the solid obtained above, which was collected byfiltration and washed with diethyl ether, was added to a mixed solutionof p-toluenesulfonic acid (catalytic amount) in ethanol (5 ml) and themixture was refluxed for one hour. After removal of ethanol, the residuewas pulverized with diethyl ether and collected by filtration. Thepowder was recrystallized from a mixture of acetone and ethyl acetate togive colorless granules (114.8 mg) of ethyl2-methyl-4-(2-methoxyphenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 219° to 220° C.

(8) To a suspension of diethyl2-methyl-4-(3-hydroxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(600 mg) in ethanol (15 ml), was added sodium borohydride (63.5 mg) at0° C. under stirring and the resultant mixture was further stirred foran hour. The resultant mixture was adjusted with 0.1N hydrochloric acidto pH 3 to 4 under ice-cooling. The ethanol was distilled off underreduced pressure and the residue was extracted with ethyl acetate. Theextract was washed with water twice and an aqueous sodium chloridesolution in turn, dried over magnesium sulfate and then concentratedunder reduced pressure to give crystals (600 mg). These wererecrystallized from a mixture of ethyl acetate and diethyl ether to givepure crystals (350 mg) of diethyl2-methyl-4-(3-hydroxyphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 161.5° to 163° C.

(9) To a solution of diethyl2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(940.68 mg) in 99% ethanol (30 ml) was gradually added sodiumborohydride (113.5 mg) under stirring and this was further stirred atroom temperature for 2 hours. After removal of ethanol, the residue wasextracted with ethyl acetate and the extract was washed twice with waterand then dried. The solvent was removed from the extract to give a paleyellow oil. The oil was pulverized with n-hexane. The powder wasdissolved in ethyl acetate. After collecting by filtration of theinsoluble product, to the filtrate was added n-hexane and the mixturewas allowed to stand in refrigerator. The appearring crystals werecollected by filtration to give pale yellow granules (857.2 mg) ofdiethyl2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 125° to 126° C.

The insoluble product obtained above was collected by filtration to givepowder (33.3 mg) of ethyl2-methyl-4-(2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 232° C.

(10) To a solution of 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(2.0 g) in ethanol (40 ml) was added bit-by-bit sodium borohydride(113.5 mg) at 5° C. under stirring. The mixture was further stirred at5° C. for 30 minutes and acidified weakly with 50% acetic acid. Afterremoval of the ethanol, to the residue was added water, and the mixturewas made slightly alkaline with an aqueous solution of sodiumbicarbonate, allowed to stand and then filtered, when it became clear.The precipitate (1.58 g) was collected by filtration and recrystallizedfrom a mixture of ethanol and diisopropyl ether to give yellowish-orangegranules (0.99 g) of 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 167° to 169° C.

(11) To a suspended solution of benzyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.2 g) in ethanol (20 ml) was added sodium borohydride (60.6 mg) underice-cooling and stirred, and further stirred for an hour at 0° C. andanother an hour at 3° C. The reaction mixture was added with water andthe resultant mixture was adjusted to pH 6 to 7 with 2N hydrochloricacid, and the solvent was distilled off. The residue was extracted withethyl acetate and washed with water and dried. After removal of thesolvent, the resultant oil (1.3 g) was purified by column chromatographyon silica gel with an eluent (a mixture of ten parts of benzene and onepart of ethyl acetate by volume) to give an oil which was immediatelycrystallized. The resultant crystals were recrystallized from a mixtureof diethyl ether and n-hexane and dissolved in benzene. The benzenesolution was subjected to azeotropic process five times to give purecrystals of benzyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 51° to 57° C.

(12) To a suspension of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.13 g) in ethanol (15 ml) was added sodium borohydride (80 mg) withstirring under ice-cooling, and this mixture was further stirred for anhour at the same temperature. The reaction mixture was adjusted withdilute hydrochloric acid to pH 6 under ice-cooling and then the solventwas distilled off. To the residue was added water and the aqueousmixture was extracted with diethyl ether. The extract was washed withwater and dried over magnesium sulfate. Removal of the solvent gave anoil, which was crystallized by treating with n-hexane. These wererecrystallized from a mixture of diethyl ether and n-hexane to give purecrystals (900 mg) of 2-ethoxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 99° to 100° C.

(13) To a solution of 2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.5 g) in ethanol (15 ml) was added sodium borohydride (112 mg) understirring and ice-cooling, and this mixture was further stirred for 20minutes at the same temperature. The reaction mixture was adjusted with0.1N hydrochloric acid to pH 6 to 7 under ice-cooling, and concentratedunder reduced pressure. To the residue was added ethyl acetate andwater, and the aqueous layer was further washed with ethyl acetatetwice. The extract obtained above and the washings were put together,washed with water, dried over magnesium sulfate, and concentrated underreduced pressure to give an oil (1.48 g) of2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν (cm⁻¹): 3390, 1730, 1680, 1650, 1600, 1520,1460, 1345, 1200, 1100, 1025, 900, 780, 740, 700.

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.2 (3H, t, J=7 Hz), 2.2 (3H, s),2.38 (3H, s), 2.66 (2H, t, J=6 Hz), 3.53 (2H, s), 3.97 to 4.26 (4H, m),5.14 (1H, s), 7.28 to 8.15 (10H, m).

Thus obtained oil was dissolved into diethyl ether, and 21% ethanolichydrochloric acid (225 mg) was added to the solution. A precipitatingoil substance was washed with diethyl ether several times by decantationand pulverized to give powder (540 mg) of2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylatehydrochloride which began to decompose at 89° C. with turning to brown.

I.R. Spectrum (Nujol): ν (cm⁻¹): 3300, 2600, 1680, 1525, 1375, 1350,1200, 1095, 740, 700.

(14) To a mixture of powder (329 mg) of methyl4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylatein ethanol (10 ml) was added sodium borohydride (25.11 mg) underice-cooling. After further stirring for 50 minutes, the mixture wasadjusted to pH 4 to 5 with dilute hydrochloric acid. After removal ofthe ethanol, water was added to the residue, which was extracted withethyl acetate. The ethyl acetate layer was washed with water and driedand the residual crystals (about 280 mg) were dissolved in a mixture ofdiethyl ether and n-hexane and kept in a refrigerator to give purecrystals (184 mg) of methyl4-(2-chlorophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 187° to 188° C.

(15) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1 g) in 99% ethanol (20 ml) was added sodium borohydride (115 mg)under stirring and the mixture was further stirred at room temperaturefor 5 hours. The resultant mixture was acidified with dilutehydrochloric acid. After removing ethanol, water was added to theresidue and the mixture was washed with diethyl ether. The aqueous layerwas basified with an aqueous solution of sodium bicarbonate andextracted with ethyl acetate. The extract was washed with water anddried. The solvent was removed from the extract to give greenish brownoil (0.8087 g) of a mixture including diethyl2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate(one part) and ethyl2-methyl-4-(2-nitrophenyl)-5-oxo-6-[2-(N,N-diethylamino)ethyl]-1,4,5,7-tetrahydropyrrolo[3,4-b]pyridine-3-carboxylate(one part). After dissolving the mixture in ethanol, the solution wasrefluxed for 5 hours. The removal of the solvent gave crystals. Thesewere recrystallized from ethanol to give yellow needles (729.9 mg) ofethyl2-methyl-4-(2-nitrophenyl)-5-oxo-6-[2-(N,N-diethylamino)ethyl]-1,4,5,7-tetrahydropyrrolo-[3,4-b]pyridine-3-carboxylate,m.p. 187° to 188° C.

(16) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.2 g) in 95% ethanol (15 ml) was added sodium borohydride (115 mg) andstirred overnight at room temperature. The resultant mixture was weaklyacidified with dilute hydrochloric acid and the ethanol was removed fromthe mixture. The residue was basified with an aqueous solution of sodiumbicarbonate and then extracted with ethyl acetate. The extract waswashed with water and dried over magnesium sulfate. The solvent wasdistilled off to give an oil of diethyl2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.This oil was dissolved in 95% ethanol (15 ml) and the solution wasrefluxed for 3 hours. Ethanol was removed from the solution to give ared oil. The oil was pulverized and recrystallized from a mixture ofethanol and diethyl ether to give an orange crystals (0.5998 g) of ethyl2-methyl-4-(2-nitrophenyl)-5-oxo-6-(2-hydroxyethyl)-1,4,5,7-tetrahydropyrrolo-[3,4-b]pyridine-3-carboxylate.The product was further recrystallized from a mixture of ethanol anddiethyl ether to give pure pale orange granules, m.p. 210° to 211° C.

EXAMPLE 6

(1) To a solution of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(759.7 mg) in dried pyridine was dropwise added a solution of acetylchloride (313.5 mg) in methylene chloride under cooling and stirring.The mixture was stirred overnight at room temperature. After removingthe solvent, water was added to the residue, and the mixture was weaklyacidified with dilute hydrochloric acid, and then extracted with diethylether. The extract was washed with an aqueous saturated sodium chloridesolution and water in turn, and dried. The solvent was removed from theextract to give viscous oil (0.99 g). The oil was allowed to stand topulverize and the crystals were washed with n-hexane and collected byfiltration to give crude product (0.6931 g) of diethyl2-methyl-4-(2-chlorophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate.The crude product was recrystallized from a mixture of diethyl ether andn-hexane to give the pure product, m.p. 98° C.

(2) A mixed solution of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(0.3798 g), pyridine (0.791 g) and succinic anhydride (0.1501 g) indioxane (5 ml) was refluxed for 4.5 hours. The resultant solution wasconcentrated, acidified with dilute hydrochloric acid and extracted withdiethyl ether. The extract was washed with dilute hydrochloric acid andwater in turn. The diethyl ether extract was back-extracted with anaqueous saturated sodium bicarbonate solution and the aqueous solutionwas washed with diethyl ether. The aqueous solution was acidified withdilute hydrochloric acid to precipitate crystals. The crystals werecollected by filtration, washed with water and then dried to givediethyl2-methyl-4-(2-chlorophenyl)-6-(3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(419.3 mg), m.p. 130° to 131° C.

(3) To a solution of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(0.7050 g) in pyridine (15 ml) was dropwise added a solution of ethyl5-chloroformylpentanoate (0.7706 g) in methylene chloride underice-cooling and the mixture was stirred at room temperature for 2.5hours. After removing the pyridine water was added to residue and themixture was extracted twice with ethyl acetate. The extract was washedwith dilute hydrochloric acid, an aqueous sodium bicarbonate solutionand water in turn, and then dried. The solvent was removed from theextract to give a yellow oil (1.0996 g) The oil was pulverized andrecrystallized from a mixed solution of diethyl ether and n-hexane togive colorless flakes (0.7311 g) of diethyl2-methyl-4-(2-chlorophenyl)-6-(5-ethoxycarbonylvaleryl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 91° to 92° C.

(4) To a mixture of sodium 3-(N-methyl-N-benzylamino)propionate (2.0 g)in diethyl ether (40 ml) was added thionyl chloride (10 ml) withstirring under ice-cooling. The resultant mixture was stirred at roomtemperature for 3 hours, heated under reflux for 2 hours andconcentrated under reduced pressure to give a solid containing3-(N-methyl-N-benzylamino)propionyl chloride. A suspension of thusobtained solid in methylene chloride (5 ml) was added to a solution ofdiethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(0.76 g) in pyridine (5 ml) with stirring under ice-cooling. The mixturewas stirred for an hour under ice-cooling and concentrated under reducedpressure, and water was added to the residue. The aqueous mixture wasextracted with ethyl acetate and the extract was washed with water,dried and concentrated under reduced pressure to give a brown oil (1.55g). The oil was subjected to column chromatography on silica gel with aneluent [a mixture of 2 parts of benzene and one part of ethyl acetate byvolume] to give an oily substance. The oily substance was allowed tostand overnight to give crystals. These crystals were washed withn-hexane and recrystallized from a mixture of diethyl ether and n-hexaneto give pure crystals of diethyl2-methyl-4-(2-chlorophenyl)-6-{3-(N-methyl-N-benzylamino}propionyloxy)methyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 86° to 87° C.

(5) To a mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(2.35 g) in pyridine (30 ml), was dropwise added a solution of acetylchloride (942 mg) in methylene chloride (5 ml) under stirring andice-cooling over the period of 7 minutes. The mixture was furtherstirred for 70 minutes at room temperature. The pyridine was distilledoff under reduced pressure and ethyl acetate was added to the residue.The resultant mixture was washed twice with water and adjusted to pH 4with hydrochloric acid and then an aqueous solution of sodium chloride,dried and concentrated under reduced pressure to give an oily substance.This oily substance was crystallized by treating with a mixture ofdiethyl ether and a small amount of n-hexane, and collected crudecrystals (2.5 g) were washed with n-hexane and thus obtained crystalswere recrystallized from diethyl ether to give pure crystals (1.78 g) ofdiethyl2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 89° to 90° C.

(6) To a solution of diethyl2-methyl-4-(3-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.95 g) in dried pyridine (25 ml) was dropwise added a solution ofacetyl chloride (785 mg) in methylene chloride (5 ml) under ice-coolingand stirring over the period of 10 minutes. The mixture was furtherstirred for 50 minutes at room temperature. After removing the solvent,the residue was dissolved in ethyl acetate. The extract was washed withwater five times and an aqueous solution of sodium chloride in turn, anddried over magnesium sulfate. The solvent was removed from the extractto give a red oil (2.47 g). The oil was crystallized by treating withdiethyl ether, and the crystals were washed with n-hexane and collectedby filtration to give crude crystals (2 g). These crystals weredissolved in diethyl ether and the mixture was filtered on silica gel.The filtrate was concentrated under reduced pressure and the crystallineresidue was recrystallized from a mixture of diethyl ether and n-hexaneto give pure crystals (1.45 g) of diethyl2-methyl-4-(3-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 133° to 135° C.

(7) To a mixture of 2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate(630 mg) in pyridine (10 ml) was added a solution of acetyl chloride(146 mg) in methylene chloride (3 ml) under stirring and ice-cooling.The resultant mixture was further stirred at 50° to 60° C. for 2 hours.After removing the pyridine, water and ethyl acetate were added to theresidue and the aqueous layer was adjusted to pH 4. The organic layerwas separated, dried over magnesium sulfate and concentrated underreduced pressure to give an oily substance (800 mg). This oily substancewas subjected to column chromatography on silica gel with an eluent [amixture of 2 parts of benzene and 1 part of ethyl acetate by volume] togive an oil (620 mg) of 2-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-acetoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν (cm⁻¹): 3370, 1747, 1690, 1650, 1615, 1530,1480, 1350, 1210, 1100, 1045, 740, 700.

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.18 (3H, t, J=7 Hz), 2.18 (6H,s), 2.36 (3H, s), 2.6 (2H, t, J=6 Hz), 3.5 (2H, s), 4.06 (2H, q, J=7Hz), 4.15 (2H, t, J=6 Hz), 5.13 (1H, s), 5.31 (2H, s), 6.7 (1H, m), 7.23to 8.08 (9H, m).

Thus obtained oil (580 mg) was dissolved in diethyl ether, and to theresultant solution was bit by bit added a diethyl ether solution ofmaleic acid to give a precipitating oil. This oil was washed withdiethyl ether twice by decantation and pulverized by n-hexane to givepowder (405 mg) of2-(N-methyl-N-benzylamino)ethyl-2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-acetoxymethyl-1,4-dihydropyridine-3-carboxylatemaleate, m.p. 52° to 65° C.

(8) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.95 g) in pyridine (25 ml) was dropwise added a solution of benzoylchloride (2.0 g) in methylene chloride (5 ml) over 5 minutes at 5° to 6°C. with stirring. The resultant mixture was stirred for 15 minutes atthe same temperature and then at room temperature for 2 hours, andfollowed by stirring at 50° C. for an hour and a half. After thereaction was over, the pyridine was distilled off and to the residue wasadded ethyl acetate and water. The ethyl acetate layer was separated,washed with dil. hydrochloric acid twice and then aqueous solution ofsodium bicarbonate, and dried over magnesium sulfate. The solvent wasremoved and the residue was soon crystallized by treating with diethylether and collected by filtration. These crude crystals were washed witha mixture of diethyl ether and a small amount of ethyl acetate to givecrystals, which was recrystallized from ethyl acetate (25 ml) to givepowders of diethyl2-methyl-4-(2-nitrophenyl)-6-benzoyloxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 156° to 157° C.

(9) To a solution of diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.95 g) in pyridine (25 ml) was dropwise added over 5 minutes asolution of p-chlorophenoxyacetyl chloride (3.07 g) in methylenechloride under stirring and ice-cooling. The resultant mixture wasstirred overnight under cooling with water at 20° C. After removal ofthe pyridine, water was added to the residue. The precipitated oilysubstance was extracted with ethyl acetate. The extract was adjusted topH 4 to 5 with dil. hydrochloric acid, washed each three times withwater and then an aqueous solution of sodium bicarbonate and dried overmagnesium sulfate. The solvent was distilled off and the residual oil(4.75 g) was subjected to column chromatography on silica-gel using aneluent (benzene:ethyl acetate=10:1) to give an oil (2.65 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-(4-chlorophenoxy)acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 86° to 88° C. (recrystallized from a mixture of diisopropyletherand ethanol).

N.M.R. Spectrum(δCDCl₃ +D₂ O): ppm: 1.13 (6H, t, J=7 Hz), 2:2 (3H, s),4.03, 4.08 (4H, q, J=7 Hz), 4.73 (2H, s), 5.43 (2H, s), 5.88 (1H, s),6.53 (1H, broad s), 6.76 to 7.83 (8H, m).

EXAMPLE 7

Stirring a solution of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1395 g) in dried pyridine (10 ml) at room temperature, a solution ofp-toluenesulfonyl chloride (629.1 mg) in dried pyridine (10 ml) wasdropwise added gradually thereto. The resultant mixture was stirred atroom temperature for 1.5 hours and then heated at 80° C. for 4.5 hourswith stirring. After removal of the pyridine, water was added to theresidue and the resultant aqueous mixture was acidified with dil.hydrochloric acid and extracted twice with ethyl acetate. The extractwas washed with dil. hydrochloric acid and then water, and dried. Theresultant brown viscous oil was purified by column chromatography onsilica-gel using an eluent (benzene:diethyl ether=1:1) to give an orangeoil, which was crystallized by treating with diethyl ether. Theresultant crystals were collected by filtration and recrystallized froma mixture of diethyl ether and n-hexane to give orange-yellowish prisms(0.1926 g) of diethyl2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 87° to 88° C., which was identified with an authentic sample.

EXAMPLE 8

(1) A solution of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(0.9709 g) and hydrazine hydrate (0.1252 g) in n-propyl alcohol (10 ml)was stirred at room temperature for 30 minutes. The resultant mixturecontained mainly diethyl2-methyl-4-(2-nitrophenyl)-6-hydrazonomethyl-1,4-dihydropyridine-3,5-dicarboxylate.Then the mixture was refluxed for 6 hours. After allowing to stand theresultant solution in a refrigerator overnight, the precipitatingcrystals were collected by filtration to give ethyl2-methyl-4-(2-nitrophenyl)-5-oxo-1,4,5,6-tetrahydro-3-pyrido[2,3-d]-pyridazine-3-carboxylate(263.9 mg). The product was recrystallized from a mixture of ethanol andN,N-dimethylformamide to give the pure product, m.p. 279° to 281° C.

(2) A solution of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(592.5 mg) and p-toluenesulfonic acid (catalytic amount) in ethanol (6ml) was refluxed for 4 hours. After the resultant solution wasconcentrated, diethyl ether was added to the residue. The precipitatingcrystals were collected by filtration to give ethyl2-methyl-4-(2-chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate(317.5 mg). The crude product was recrystallized from ethyl acetate togive colorless granules (210.3 mg), m.p. 211° to 212° C.

(3) A solution of diethyl2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(400 mg) and p-toluenesulfonic acid (catalytic amount) in 99% ethanol(10 ml) was refluxed with stirring for 2 hours. After the resultantsolution was concentrated, the residue was pulverized. The powder wasrecrystallized from ethyl acetate to give colorless prisms (203.2 mg) ofethyl2-methyl-4-(2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,m.p. 232° C.

EXAMPLE 9

(1) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(379.8 mg) and triphenylphosphine (314.7 mg) in carbon tetrachloride (5ml) was refluxed for 3.5 hours. After the solvent was removed, theresidue was dried under reduced pressure to give diethyl2-methyl-4-(2-chlorophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate.To this residue in 99% ethanol (10 ml) was added N-methylpiperazine (200mg) and the solution was stirred at room temperature for 50 hours.Ethanol was removed from the reaction mixture and to the residue wasadded water. The mixture was extracted with ethyl acetate. After washingthe extract with water, the extract was back-extracted with dilutehydrochloric acid. The aqueous layer was washed with diethyl ether,basified with an aqueous solution of sodium bicarbonate, and thenextracted with ethyl acetate. The extract was washed with water, driedand then concentrated to give crude crystals (115.2 mg) of diethyl2-methyl-4-(2-chlorophenyl)-6-(N-methylpiperazin-1-yl-methyl)-1,4-dihydropyridine-3,5-dicarboxylate.The crude crystals were recrystallized from a mixture of ethanol anddiethyl ether to give colorless needles, m.p. 179° to 180° C.

(2) A mixture of diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.1395 g) and triphenylphosphine (1.1803 g) in carbon tetrachloride (10ml) was heated under reflux for 2 hours. After removing the solventunder reduced pressure, the residue was dissolved in 99% ethanol (20ml). To the solution was added N-(2-hydroxyethyl)piperazine (859 mg) andthe mixture was heated at 70° to 75° C. for 8 hours. The resultantmixture was concentrated under reduced pressure and the residue wasdissolved in ethyl acetate. The solution was washed with water and thenback-extracted with an aqueous dilute hydrochloric acid. The aqueouslayer was washed with diethyl ether, alkalized with sodium bicarbonateand then extracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate and concentrated under reducedpressure to give crude crystals (560 mg). These were recrystallized froma mixture of ethanol and diethyl ether to give pure crystals (80 mg) ofdiethyl 2-methyl-4-(2-chlorophenyl)-6-[N-(2-hydroxyethyl)piperazin-1-yl]methyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 145° to 147° C.

(3) A mixture of 2-chloroethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(8.5 g), N-methylbenzylamine (2.70 g) and triethylamine (2.6 g) inethanol (40 ml) was heated under reflux for 56 hours. After removing theethanol, the residue was dissolved in a mixture of ethyl acetate andwater. The organic layer was separated and washed with water, dried overmagnesium sulfate and concentrated under reduced pressure to give an oil(11 g). The oil was subjected to column chromatography on silica gelwith an eluent (a mixture of 10 parts of benzene and one part of diethylether by volume] to give an oil (7.35 g) of2-(N-benzyl-N-methylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3400, 1700, 1690, 1610, 1523, 1475, 1350,1275, 1197, 1092, 1055, 755, 698.

N.M.R. Spectrum (δ: CDCl₃ +D₂ O): ppm: 1.21 (9H, t, J=7 Hz), 2.21 (3H,s), 2.36 (3H, s), 2.63 (2H, t, J=6 Hz), 3.5 (2H, s), 3.65 (2H, q, J=7Hz), 3.66 (2H, q, J=7 Hz), 4.1 (2H, q), 4.18 (2H, t, J=6 Hz), 5.18 (1H,s), 6.2 (1H, s), 6.86 (1H, s), 7.16 to 8.16 (4H, m).

(4) A mixture of 2-chloroethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(20 g), diethylamine (1.75 g) and sodium iodide (60.3 mg) inn-propylalcohol (4 ml) was refluxed for 17 hours. After removal of thesolvent from the reaction mixture, water and ethyl acetate were added tothe residue. The ethyl acetate layer was washed twice with water, driedover magnesium sulfate, and concentrated to give a brown oil (2.46 g) of2-(N,N-diethylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,which was identified by converting to the corresponding 6-formylcompound (oil) and then to the corresponding 6-cyano compound, m.p. 150°to 152° C.

(5) A mixture of 2-chloroethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(1.491 g) and potassium carbonate (456.1 mg) in ethanol (30 ml) wasrefluxed for 6.5 hours. After removal of the ethanol, the residue wasextracted with ethyl acetate. The ethyl acetate layer was washed twicewith water and dried, and the solvent was distilled off to give aviscous oil (1.47 g). This oil was purified by column chromatography andthe resultant oil (0.82 g) was crystallized and recrystallized fromdiisopropyl ether to give yellow granules (0.60 g) of 2-hydroxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 98° to 100° C.

A mixture of the above obtained yellow granules (1.46 g) obtained inExample 1-12 and potassium carbonate (0.41 g) in 80% ethanol (20 ml) wasrefluxed for 6.5 hours. After removal of the ethanol, water was added tothe residue, and the mixture was acidified with dilute hydrochloric acidand extracted with ethyl acetate. The extract was washed three timeswith water, dried, and concentrated to give a brown oil (1.54 g). Thusobtained oil was subjected to column chromatography on silica gel withan eluent (a mixture of five parts of benzene and two part of ethylacetate by volume), and the fraction containing the designated substancewas concentrated to give a reddish oil (1.31 g) of 2-hydroxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.

I.R. Spectrum (film): ν(cm⁻¹): 3530, 3410, 3360 (shoulder), 1706(shoulder), 1697, 1690 (shoulder), 1532, 1480, 1356, 1275, 1208, 1100,1105, 860, 832, 785.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.0 to 1.45 (9H, m), 2.39 (3H, s), 2.2to 2.73 (1H, broad), 3.4 to 4.5 (10H, m).

(6) A mixture of diethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(388.37 mg), ethylene glycol (186.21 mg) and p-toluenesulfonic acid(catalytic amount) in absolute benzene. (5 ml) was refluxed for 45minutes under azeotropic dehydration. The reaction mixture was allowedto stand and washed twice with an aqueous solution of sodiumbicarbonate. After removal of the solvent, the residue immediatelyturned into crystals. Thus obtained crystals were recrystallized from amixture of ethanol and diisopropyl ether to give yellow pure crystals(0.32 g) of diethyl2-methyl-4-(2-nitrophenyl)-6-ethylenedioxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 152° to 153.5° C.

(7) A mixture of diethyl2-methyl-4-(2-nitro-phenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.9518 g) and triphenylphosphine (1.4425 g) in carbon tetrachloride (20ml) was refluxed for 5 hours. After removal of the solvent, the residuewas added to water and extracted with ethyl acetate. The extract waswashed with water and dried. Removal of the solvent gave anorange-yellow oil (3.63 g). This oil was subjected to columnchromatography on silica gel with an eluent (benzene:ethyl acetate=5:2)to give an oil (517 mg) of diethyl2-methyl-4-(2-nitrophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate.

(8) To a solution of an oil (517 mg) of diethyl2-methyl-4-(2-nitrophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylatein 95% ethanol (1 ml) was added sodium cyanide (93 mg), and theresultant mixture was stirred at room temperature for 2 hours. Additionof water to the reaction mixture precipitated an oil. The oil wasextracted twice with ethyl acetate, and the organic layer was washedwith water twice and with a saturated solution of sodium chloride anddried. Removal of the solvent gave a foamy oil (0.42 g), which wassubjected to column chromatography on silica gel with an eluent(benzene:ethyl acetate=5:2) to give a reddish orange oil (0.2783 g) ofdiethyl2-methyl-4-(2-nitrophenyl)-6-cyanomethyl-1,4-dihydropyridine-3,5-dicarboxylate.

I.R. Spectrum (liquid): ν(cm⁻¹): 2210.

EXAMPLE 10

(1) To a mixture of 2-allyloxybenzaldehyde (8.11 g) and ethyl4,4-diethoxyacetoacetate (12.00 g) in benzene (about 31 ml) was addedacetic acid (0.36 g) and to the resultant mixture was added each onethird portion of piperidine (0.51 g) in benzene (about 4 ml) with aninterval of 20 minutes. After refluxing for 2.5 hours the mixture wascooled to room temperature and benzene (50 ml) was added thereto. Theresultant mixture was washed three times with water and dried overmagnesium sulfate. Removing of the solvent, a red oil was gained and tothis oil was added ethyl 3-aminocrotonate (8.56 g). The resultantmixture was warmed at 55° to 60° C. for 6.5 hours under stirring andfurther for 2 hours at 72° to 75° C. and finally for 2.5 hour at 105° to107° C. The reaction mixture was subjected to column chromatography onsilica gel with an eluent to give an oil (19.38 g) from the eluate. Theoil (3.0 g) was further purified on silica gel column chromatographywith an eluent (benzene:ethyl acetate=20:1) to give an oil (1.77 g) ofdiethyl2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate

I.R. Spectrum (liquid): ν(cm⁻¹): 3430, 1695, 1650, 1618, 1490, 1371,1280, 1095, 930, 760.

N.M.R. Spectrum (δ, CDCl₃): ppm: 1.0-1.5 (12H, m), 2.28 (3H, s), 3.4-4.3(8H, m), 5.35 (1H, s), 6.17 (1H, s), ca 4.5, ca 5-5.6, ca 5.7-6.4 (5H,m), 6.5-7.4 (5H, m).

(2) To a solution of diethyl2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.5 g) in acetone (13 ml) was added 6N-hydrochloric acid (1.5 ml) withstirring and the resultant mixture was further stirred for an hour and45 minutes at room temperature. The solvent was removed, and addition ofwater to the residue resulted a yellowish suspension with precipitationof an oil, which was immediately solidified. After being allowed tostand for about 10 minutes, the precipitated solids were collected byfilteration and washed with water and dried. Thus obtained crudecrystals were recrystallized from a mixture of diisopropyl ether andacetone to give orange-yellow granules of diethyl2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 129° to 131° C.

(3) A mixture of diethyl2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(4.53 g), hydroxylamine hydrochloride (866.9 mg), sodium acetate (1.2093g) in acetic acid was stirred at room temperature for an hour. Aceticanhydride (3.5 ml) was added to the mixture and the resultant mixturewas stirred at 93° to 98° C. for 3 hours. The acetic acid was distilledoff under reduced pressure, and the residue was neutralized with asaturated aqueous solution of sodium bicarbonate and extracted twicewith methylene chloride. The extract was washed with water twice anddried. Removal of the solvent gave a brown oil (6.42 g), which wasimmediately crystallized. The crystals were pulverized with diisopropylether to give yellow powder (3.21 g), which was recrystallized from 90%methanol to give orange-yellow crystals of diethyl2-methyl-4-(2-allyloxyphenyl)-6cyano-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 143° to 145° C.

(4) To a solution of diethyl2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(4.70 g) in ethanol (100 ml) was gradually added at 4° C. sodiumborohydride (445.2 mg) and the resultant mixture was stirred at 4° C.for 1.5 hours under ice-cooling. The reaction mixture was acidified with50% acetic acid and ethanol was removed. To the residue was added waterand the aqueous mixture was stirred for 10 minutes. The powder wascollected by filtration and washed with water to give crude crystals(4.49 g), which were recrystallized from methanol to give yellowcrystals of diethyl2-methyl-4-(2-allyloxyphenyl)-6-hydroxymethyl-1,4-dihydropiridine-3,5-dicarboxylate,m.p. 124° to 126° C.

EXAMPLE 11

(1-i) To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl4,4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g) in benzene(15 ml) was added portionwise each one third of a solution of piperidine(390 mg) in benzene (5 ml) for each 20 minutes' interval. The mixturewas heated to reflux for 2 hours and the resulting water was removed offazeotropically during the reaction course. After cooling, the reactionmixture was shaken with a mixture of benzene (50 ml) and water (30 ml),and the organic layer was separated and washed with diluted aqueoussodium bicarbonate solution and water. The aqueous washings wereextracted with benzene (30 ml). The benzene extract was combined withthe above organic layer, washed with water, dried over magnesium sulfateand evaporated to dryness under reduced pressure. The oily residue (14.8g) was chromatographed on a column of silica-gel (200 g) and eluted witha mixture of benzene and ethyl acetate (25:1, v/v) to give an oilymethyl 2 -(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.90 g). Thethin layer chromatogram and N.M.R. spectrum of this product show that itconsisted of a mixture of two stereoisomers.

N.M.R. δ ppm. (CDCl₃) 3.4 (s, 3H); 3.48 (s, 3H); 3.78 and 3.90 (3H, eachs); 4.83 and 5.09 (1H, each s); 7.43-7.8 (m, 4H); 8.0 and 8.15 (1H, eachs).

(1-ii) A mixture of above obtained methyl2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.8 g) and methyl3-aminocrotonate (2.98 g) was heated under stirring at around 60° C. for2 hours, and then the temperature was gradually raised and kept at 100°to 103° C. for 10 hours. During the reaction course, n-propylalcohol (3ml) was added into the reaction mixture for dissolving the resultingcrystalline mass. The reaction mixture was dissolved in a mixture ofdiisopropyl ether (9 ml) and methanol (3 ml) and allowed to stand for awhile to give pale brown fine crystals of dimethyl2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(6.39 g), an aliquot of which was recrystallized from a mixture ofdiisopropyl ether and methanol (1:1, v/v) to give the pure crystals mp.133°-134.5° C.

N.M.R. δ ppm. (CDCl₃) 3.4 (3H, s), 3.48 (3H, s), 3.78 and 3.9 (3H, s),4.83 and 5.09 (1H, s), 7.43 to 7.8 (4H, m), 8.0 and 8.15 (1H, s).

(2-i) To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15ml) was added portionwise each one third portion of a solution ofpiperidine (306 mg) in benzene (5 ml) for each 20 minutes' interval, andthe mixture was heated to reflux for 3 hours under removing offazeotropically the resulting water. After cooling, the reaction mixturewas diluted with additional benzene (25 ml), washed three times withwater and successively with diluted aqueous sodium bicarbonate solution,water and saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureto give reddish oil (12.7 g) of crude ethyl2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was usedin the following reaction without any further purification.

(2-ii) A mixture of ethyl2-(2-methoxycarbonylbenzylidene)-4,4-diethoxyacetoacetate (12.7 g) andethyl 3-aminocrotonate (5.03 g) was heated under stirring at around 60°to 70° C. for 1.5 hours and then the temperature was raised gradually,to keep at 90° C. for 3.5 hours and finally at 110° C. for 4.5 hours.After cooling, the reaction mixture was dissolved in ethyl acetate (50ml), washed twice with water, dried over magnesium sulfate andevaporated to dryness under reduced pressure to give reddish brown oilyresidue (12.8 g). The oil was treated with a mixture of diisopropylether and n-hexane (1:10, v/v) to give light brown crystalline powder ofdiethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(3.5 g). An additional crop (0.33 g) was recovered from the motherliquor, and further crop (1.6 g) was recovered from the whole motherliquor by subjecting the residual oil (8.0 g) to column chromatographyon silica-gel (240 g), and eluted with a mixture of benzene and ethylacetate (15:1 and 10:1, v/v), (total yield 5.43 g). A 300 mg portion ofthe first crop was recrystallized from 3 ml of n-hexane to give 290 mgof the pure crystals, mp 94°-95° C.

N.M.R. δ ppm (CDCl₃): 1.25 (6H, t, J=7 HZ), 1.15 (6H, t, J=7 HZ), 2.33(3H, s), 3.92 (3H, s), 3.42-4.23 (8H, m), 6.04 (1H, s), 6.11 (1H, s),6.6 (1H, broad s), 7.0-7.8 (4H, m).

(3) To a solution of 2-N-methylsulfamoylbenzaldehyde (1.75 g), methyl4,4-dimethoxyacetoacetate (1.70 g), and acetic acid (0.1 g) in benzene(5 ml) was added a solution of piperidine (90 mg) in benzene (3 ml) in asimilar manner to the aforementioned Examples (1-i) and (2-i), and themixture was heated to reflux for 2 hours. During the reaction course,the resulting water was removed off azeotropically. After cooling, thereaction mixture was diluted with benzene (15 ml), washed twice withdiluted aqueous sodium bicarbonate solution and in turn with water andsaturated aqueous sodium chloride solution, dried over magnesium sulfateand then evaporated to dryness under reduced pressure to give reddishyellow oil (3.46 g). The oil was chromatographed on a column ofsilica-gel (69 g) and eluted with a mixture of benzene and ethyl acetate(3.5:1, v/v) to give an oily methyl2-(2-N-methylsulfamoylbenzylidene)-4,4-dimethoxyacetoacetate (1.12 g). Amixture of thus obtained oilymethyl-2-(2-N-methylsulfamoylbenzylidene)-4,4-dimethoxyacetoacetate (1.0g) and methyl 3-aminocrotonate (355 mg) was heated at 60° C. for 3hours, and the temperature was raised gradually to 100° C. during 1.5hours and kept at 100° C. for 5.5 hours. The reaction mixture waschromatographed on a column of silica-gel (33 g) and eluted with mixtureof benzene and ethyl acetate (5:1, v/v) to give an oily dimethyl2-methyl-4-(2-N-methylsulfamoylphenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(840 mg).

N.M.R. δ ppm (CDCl₃): 2.37 (3H, s), 2.65 (3H, d, J=3 Hz), 3.40 (3H, s),3.45 (3H, s), 3.63 (3H, s) 3.65 (3H, s), 4.77 (1H, q, J=3 Hz), 5.11 (1H,s), 6.01 (1H, s), 6.88 (1H, broad s), 7.35-7.75 (4H, m).

(4) A mixture of methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate(15.19 g) and methyl 3-aminocrotonate (6.50 g) was heated at 60° to 63°C. for 6 hours and at 100° to 105° C. for 4 hours and 45 minutes. Theresulting crystalline mass was triturated with methanol and collected byfiltration to give crystals of dimethyl2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(12.04 g). Thus obtained crystals (1.07 g) were recrystallized frommethanol (5 ml) to give pure crystals (0.93 g), m.p. 132° to 133° C.

N.M.R. δ ppm (CDCl₃): 2.36 (3H, s), 3.40 (3H, s), 3.44 (3H, s), 3.56(3H, s), 3.66 (3H, s), 5.76 (1H, s), 5.99 (1H, s), 6.85 (1H, broad s),7.1 to 7.8 (4H, m).

(5) A mixture of 2-nitrobenzaldehyde (6.8009 g), methyl4,4-dimethoxyacetoacetate (8.7204 g), acetic acid (0.5405 g) andpiperidine (0.4598 g) in benzene (30 ml) was heated to reflux for 2hours under azeotropic dehydration. The reaction mixture was dilutedwith benzene (100 ml), washed twice with water, and in turn with dilutedaqueous sodium bicarbonate solution and water, dried over magnesiumsulfate and evaporated to dryness under reduced pressure to give crudeoily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g).A mixture of thus obtained crude oil (15.23 g) and ethyl3-aminocrotonate (6.6840 g) was heated at around 65° C. for 6 hours andthen at 98° to 100° C. for 5 hours. The resultant viscous brown oil wasdissolved in ethyl acetate, washed three times with water, dried overmagnesium sulfate and evaporated to dryness under reduced pressure togive brown oil (19.40 g). The residual oil was crystallized bytrituration with methanol (10 ml) to give yellowish crystalline powder(12.77 g) of ethyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate.An additional 0.53 g of crystals was recovered from the mother liquor.Recrystallization from methanol gave yellowish granules, m.p. 122°-124°C.

N.M.R. δ ppm (CDCl₃): 1.15 (3H, t, J=7.5 Hz), 2.38 (3H, s), 3.40 (3H,s), 3.45 (3H, s), 3.60 (3H, s), 4.04 (2H, q, J=7.5 Hz), 4.08 (2H, q,J=7.5 Hz), 5.83 (1H, s), 5.98 (1H, s), 6.77 (1H, broad s), 7.1 to 7.85(4H, m).

(6) To a solution of 2-nitrobenzaldehyde (6.80 g), methyl4,4-dimethoxyacetoacetate (8.72 g) and acetic acid (0.54 g) in benzene(30 ml), was added piperidine (0.46 g), in a similar manner toaforementioned examples (1-i) and (2-i), and the mixture was heated toreflux for 2 hours under azeotropic dehydration. The reaction mixture,after cooling, was diluted with benzene (100 ml), washed three timeswith water, and in turn with diluted aqueous sodium bicarbonate solutionand water, dried over magnesium sulfated and evaporated to dryness underreduce pressure to give oily methyl2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (14.73 g). A mixture ofthe above obtained oil (14.70 g) and isopropyl 3-aminocrotonate (7.09 g)was heated at 60° to 63° C. for 2 hours and at 85° to 90° C. for about10 hours. The reaction mixture was treated with ethyl acetate to giveyellowish crystals which were collected by filtration and washed withmethanol. The filtrate was concentrated and the residue was treated withmethanol to give additional crystals. The combined crystals (11.10 g)were recrystallized from methanol to give pure crystals of isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate,m.p. 143°-145° C.

N.M.R. δ ppm (CDCl₃): 0.99 (3H, d, J=6 Hz), 1.24 (3H, d, J=6 Hz), 2.39(3H, s), 3.37 (3H, s), 3.45 (3H, s), 3.60 (3H, s), 4.96 (1H, hept., J=6Hz), 5.88 (1H, s), 5.96 (1H, s), 6.82 (1H, s), 7.1 to 7.8 (4H, m).

(7) To a mixture of 3-nitrobenzaldehyde (7.56 g), methyl4,4-dimethoxyacetoacetate (9.69 g) and acetic acid (600 mg) in benzene(25 ml) was added portionwise each one fifth portion of piperidine (851mg) in benzene (5 ml) for each 20 minutes interval and the mixture washeated to reflux for 4 hours under azeotropic dehydration. Aftercooling, the reaction mixture was diluted with benzene (50 ml), washedtwice with diluted aqueous sodium bicarbonate solution, and in turn,with water and saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and evaporated to dryness under reduced pressure togive crude reddish brown oilymethyl(3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which wasused in the following reaction without any further purification. Amixture of above oil (17.82 g) and methyl 3-aminocrotonate (6.33 g) washeated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hoursand 45 minutes. The reaction mixture was chromatographed on a column ofsilica-gel (440 g) and eluted with a mixture of benzene and ethylacetate (10:1, v/v) to give crystalline product (10.46 g) of dimethyl2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate.Thus obtained crystals (720 mg) were recrystallized from diisopropylether (10 ml) to give pure specimen (560 mg), mp 99° to 100° C.

N.M.R. δ ppm (CDCl₃): 2.47 (3H, s), 3.52 (3H, s), 3.57 (3H, s), 3.77(3H, s), 5.25 (1H, s), 6.1 (1H, s), 6.98 (1H, broad s), 7.38 to 8.17(4H, m).

(8) To a solution of 3-nitrobenzaldehyde (4.53 g), 2-benzyloxyethylacetoacetate (7.79 g) and acetic acid (360 mg) in benzene (15 ml), wasadded a solution of piperidine (306 mg) in benzene (5 ml), in a similarmanner to the aforementioned Example (1-i), and the mixture was heatedto reflux for 2.5 hours under azeotropic dehydration. The reactionmixture was left to cool and diluted with benzene (50 ml), washed withwater, diluted aqueous sodium bicarbonate solution and water, dried overmagnesium sulfate and then evaporated to dryness under reduced pressureto give brown oily 2-benzyloxyethyl 2-(3-nitrobenzylidene)acetoacetate(12.58 g). The mixture of the above obtained oil (12.58 g) and ethyl3-amino-4,4-diethoxycrotonate (8.47 g) was heated at 100° to 102° C. for4 hours and at 110° to 115° C. for 6.5 hours. After cooling, thereaction mixture was dissolved in ethyl acetate, washed twice with waterand saturated aqueous sodium chloride solution, dried over magnesiumsulfate and evaporated to dryness under reduced pressure. The residualbrown oil (19.04 g) was chromatographed on a column of silica-gel (570g) and eluted with a mixture of benzene and ethyl acetate (13:1, v/v) togive oily 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(9.64 g).

N.M.R. δ pp. (CDCl₃): 1.17 (6H, t, J=7 Hz), 1.23 (3H, t, J=7 Hz), 2.35(3H, s), 3.43 to 4.4 (10H, m), 4.5 (2H, s), 5.18 (1H, s), 6.86 (1H,broad s), 7.33 to 8.13 (9H, m).

EXAMPLE 12

(1) To a solution of dimethyl2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(6.0 g) in acetone (60 mg) was added 6N hydrochloric acid (6 ml), andthe resultant mixture was stirred for 3 hours at room temperature. Thereaction mixture was diluted with water (30 ml), and adjusted to pH 7.5with an aqueous sodium bicarbonate solution, and acetone was distilledoff under reduced pressure. The resultant crystalline mass was crushedas finely as possible with a glass rod, washed with an additional water(100 ml), collected by filtration, further washed thoroughly with water,and air-dried to give crystalline powder of dimethyl2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(5.19 g).

N.M.R. δ ppm (CDCl₃): 2.41 (3H, s), 3.65 (3H, s), 3.75 (3H, s), 5.5 (1H,s), 7.0 (1H, s), 7.25 to 7.66 (4H, m), 10.53 (1H, s).

(2) To a solution of diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(5.03 g) in acetone (50 ml) was added 6N-hydrochloric acid (5 ml), andthe mixture was stirred for 2 hours at room temperature. After addingwater (30 ml), the reaction mixture was neutralized with an aqueoussodium bicarbonate solution and acetone was distilled off under reducedpressure. The resultant oily precipitates were extracted with ethylacetate. The ethyl acetate extracts were washed with water, saturatedaqueous sodium chloride solution, dried over magnesium sulfate andevaporated to dryness under reduced pressure to give reddish oil ofcrude diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(4.26 g), which was used in a succeeding reaction without furtherpurification.

N.M.R. δ ppm (CDCl₃): 1.1 (3H, t, J=7 Hz), 1.8 (3H, t, J=7 Hz), 2.37(3H, s), 3.93 (3H, s), 3.9 to 4.28 (4H, m), 6.2 (1H, s), 6.98 (1H, s),7.1 to 7.8 (4H, m), 10.2 (1H, s).

(3) A mixture of a solution of dimethyl2-methyl-4-(2-N-methylsulfamoylphenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(600 mg) in acetone (6 ml) and 6N hydrochloric acid (0.6 ml) was stirredfor 2.5 hours at room temperature and adjusted to pH 7 to 8 with adiluted aqueous sodium bicarbonate solution, and then acetone wasdistilled off under reduced pressure. The resultant oily precipitate wastriturated with additional water to give crystalline powder of dimethyl2-methyl-4-(2-N-methylsulfamoylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(380 mg).

N.M.R. δ ppm (CDCl₃): 2.45 (3H, s), 2.65 (3H, d, J=3 Hz), 3.65 (3H, s),3.76 (3H, s), 4.6 (1H, q, J=3 Hz), 5.22 (1H, s) 7.09 (1H, broad s), 7.35to 7.85 (4H, m), 10.49 (1H, s).

(4) A mixture of a solution of dimethyl2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(10.68 g) in acetone (110 ml) and 6N hydrochloric acid (10 ml) wasstirred at 25° C. for 3 hours, which was neutralized with an aqueoussodium bicarbonate solution and acetone was distilled off under reducedpressure. The resultant reddish yellow oily precipitates weresolidified, which were cracked finely, collected by filtration, washedwith water and air dried over-night to give crude crystals of dimethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(9.33 g).

N.M.R. δ ppm (CDCl₃): 2.41 (3H, s), 3.58 (3H, s), 3.71 (3H, s), 5.88(1H, s), 7.10 (1H, broad s), 7.2 to 7.9 (4H, m), 10.43 (1H, s).

(5) To a solution of isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3,5-carboxylate(10.5 g) in acetone (105 ml) was added 6-N hydrochloric acid (15.5 ml)and the mixture was stirred at 25° C. for 2 hours. After removal ofacetone, the reesultant solution was diluted with water (50 ml), madealkaline with saturated aqueous sodium bicarbonate solution, and thenextracted with ethyl acetate. The ethyl acetate extract was washed twicewith saturated aqueous sodium chloride solution, dried over magnesiumsulfate and evaporated to dryness under reduced pressure. Thereddish-yellow oily residue (11.08 g) was triturated with a mixture ofdiethyl ether and n-hexane to give yellowish crystalline powder ofisopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(8.94 g).

N.M.R. δ ppm (CDCl₃): 0.97 (3H, d, J=6 Hz), 1.21 (3H, d, J=6 Hz), 2.43(3H, s), 3.70 (3H, s), 4.97 (1H, hept., J=6 Hz), 6.00 (1H, s), 6.95 (1H,broad s), 7.2 to 7.9 (4H, m), 10.36 (1H, s).

(6) To a solution of dimethyl2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(7.5 g) in acetone (75 ml) was added 6N hydrochloric acid (7.5 ml) andthe mixture was stirred at room temperature for 6 hours. Theprecipitates which were separated out during the reaction course werecollected by filtration to give yellowish crystals of dimethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.26 g), and the filtrate was adjusted to pH 7.5 to 8 with an aqueoussodium bicarbonate solution, and the acetone was distilled off underreduced pressure to give additional crops of orange-yellow crystals(3.84 g) of the same product, (total yield, 6.1 g). A small portion ofthe first crop was recrystallized from methanol to give pure crystals,m.p. 157°-157.5° C.

N.M.R. δ ppm (CDCl₃): 2.48 (3H, s), 3.7 (3H, s), 3.81 (3H, s), 5.3 (1H,s), 7.13 to 8.17 (5H, m), 10.5 (1H, s).

(7) To a solution of 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate(6.0 g) in acetone (60 ml) was added 6N hydrochloric acid (6 ml) and themixture was stirred at room temperature for 2 hours. The reactionmixture was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonatesolution, and acetone was distilled off under reduced pressure. Theresultant solution was diluted with water (150 ml) to separate out oilyprecipitates, which were extracted twice with ethyl acetate (100 ml and50 ml, respectively). The organic layer was washed with water, driedover magnesium sulfate and evaporated to dryness under reduced pressureto give oily 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(5.02 g).

N.M.R. δ ppm (CDCl₃): 1.25 (3H, t, J=7 Hz), 2.41 (3H, s), 4.5 (4H, s),3.5 to 4.4 (6H, m), 5.29 (1H, s), 7.3 to 8.15 (10H, m), 10.45 (1H, s).

EXAMPLE 13

(1) A mixture of dimethyl2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.4 g), hydroxylamine hydrochloride (539.3 mg) and sodium acetate(752.3 mg) in acetic acid (15 ml) was stirred at room temperature for 55minutes to formdimethyl-b-2-methyl-4-(2-cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.To the reaction mixture was added acetic anhydride (2.375 g), and themixture was heated at 110° C. for 4 hours with stirring. The reactionmixture was concentrated and treated with water (30 ml). The resultantacidic solution was adjusted to pH 7.5 to 8 with an aqueous sodiumbicarbonate solution, and extracted twice with ethyl acetate. Theorganic layer was washed with water, saturated aqueous sodium chloridesolution, and evaporated to dryness under reduced pressure. The residuewas kept overnight in a refrigerator for crystallization. The resultantcrystals were collected by filtration and washed with small portion ofcold methanol to give crystals of dimethyl2-methyl-4-(2-cyanophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate(1.71 g). Additional crop (0.9 g) was recovered from the mother liquor.The combined crystals (2.61 g) were recrystallized from methanol to givepure crystals (1.2 g), m.p. 166°-166.5° C.

N.M.R. δ ppm (CDCl₃): 2.4 (3H, s), 3.67 (3H, s), 3.75 (3H, s), 5.42 (1H,s), 7.2 to 7.62 (4H, m), 7.9 (1H, s).

(2) A mixture of diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.6 g), hydroxylamine hydrochloride (495 mg) and sodium acetate (691mg) in acetic acid (20 ml) was stirred at room temperature for an hourto form diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.To the reaction mixture was added acetic anhydride (2.18 and the mixturewas heated at 110° C. for 3.5 hours with stirring. Acetic acid wasdistilled off under reduced pressure from the reaction mixture and theresultant residue was adjusted to pH 8 with an aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The ethyl acetateextracts were washed with water, and saturated aqueous sodium chloridesolution, dried over magnesium sulfate and then evaporated to dryness.The resultant oil (2.88 g) was chromatographed on a column of silica-gel(72 g), and eluted with a mixture of benzene and ethyl acetate (10:1,v/v) to give an oil (1.6 g), which was triturated with diisopropyl ether(3 ml) to give crystalline powder (1.3 g). Recrystallization from amixture (20 ml) of diisopropyl ether and ethanol (15:1, v/v) gave purecrystals of diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate(1.03 g), mp 126° to 127° C.

N.M.R. δ ppm (CDCl₃): 1.15 (3H, t, J=7 Hz), 1.24 (3H, t, J=7 Hz), 2.33(3H, s), 3.98 (3H, s), 3.90 to 4.38 (4H, q, J=7 Hz), 6.22 (1H, s), 7.2to 7.88 (4H, m).

(3) A mixture of dimethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(3.6 g), hydroxylamine hydrochloride (764 mg) and sodium acetate (1.06g) in acetic acid (20 ml) was stirred at room temperature for 45 minutesto form dimethyl2-methyl-4-(2-nitrophenyl)-6-hydroxyliminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.To the reaction mixture was added acetic anhydride (3.37 g) and themixture was stirred at room temperature for 15 minutes and then heatedat 100° C. for 3 hours with stirring. After removal of the acetic acid,the residue was adjusted to pH 7.5 with an aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The extract was washed twicewith water and saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated to dryness under reduced pressure. Theresultant oil (3.80 g) was chromatographed on a column of silica-gel(110 g) and eluted with a mixture of benzene and ethyl acetate (9:1,v/v) to give crystals (2.05 g), which were recrystallized from a mixtureof ethyl acetate (12 ml) and n-hexane (6 ml) to give yellow granules ofdimethyl2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate(1.19 g), mp 170.5° to 171.5° C.

N.M.R. δ ppm (CDCl₃) 2.37 (3H, s), 3.6 (3H, s), 3.7 (3H, s), 5.9 (1H,s), 7.34 to 7.83 (4H, m).

(4) A mixture of isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium acetate(1.0664 g) in acetic acid (20 ml) was stirred at room temperature for anhour to form isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.To the reaction mixture was added acetic anhydride (3.37 g) and themixture was heated at 95° to 100° C. for 6 hours. After removal of theacetic acid, water was added to the residue and the mixture wasextracted with ethyl acetate. The extract was washed with water, anaqueous sodium bicarbonate solution and water in turn, dried overmagnesium sulfate and evaporated to dryness under reduced pressure. Theresidual oil (3.69 g) was chromatographed on a column of silica-gel (100g), and eluted with a mixture of benzene and ethyl acetate (5:1, v/v) togive an oil of isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate(2.0 g), which was left in a refrigerator for several days tocrystallize. Recrystallization from methanol gave pure crystals, m.p.175.5°-176.5° C.

N.M.R. δ ppm (CDCl₃): 0.91 (3H, d, J=6 Hz), 1.17 (3H, d, J=6 Hz), 2.33(3H, s), 3.65 (3H, s), 4.9 (1H, hept., J=6 Hz), 5.95 (1H, s), 6.8 (1H,broad s), 7.23 to 7.85 (4H, m).

(5) A mixture of dimethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.0 g), hydroxylamine hydrochloride (424.3 mg) and sodium acetate(591.8 mg) in acetic acid (12 ml) was stirred at room temperature for 80minutes to form dimethyl2-methyl-4-(3-nitrophenyl)-6-hydroxy-iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.To the reaction mixture was added acetic anhydride (1.87 g) and themixture was heated at 110° C. for 3.5 hours with stirring. The reactionmixture was evaporated to form crystalline mass which was neutralized bytreating with diluted aqueous sodium bicarbonate solution and thecrystalline mass were pulverized, collected by filtration and washedthoroughly with water to give crystals (1.92 g). Recrystallization froma mixture of methanol and ethyl acetate gave pure crystals of dimethyl2-methyl-4-(3-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate(1.04 g), mp 206° to 207° C. An additional crop was recovered from themother liquor of above recrystallization (0.6 g).

N.M.R. δ ppm (CDCl₃): 2.4 (3H, s), 3.65 (3H, s), 3.78 (3H, s), 5.12 (1H,s), 6.76 (1H, broad s), 7.36 to 8.1 (4H, m).

(6) A mixture of 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(2.44 g), hydroxylamine hydrochloride (377 mg) and sodium acetate (526mg) in acetic acid (15 ml) was stirred at room temperature for an hourto form 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.To the reaction mixture was added acetic anhydride (1.66 g) and themixture was stirred at room temperature for an hour and then heated at100° C. for 3 hours with stirring. After removal of the acetic acid, theresidue was adjusted to pH 7.5 with aqueous sodium bicarbonate solutionand extracted twice with ethyl acetate. The extracts were washed twicewith water, and saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated to dryness in vacuo. The residual brownoil (2.6 g) was chromatographed on a column of silica-gel (78 g) andeluted with a mixture of benzene and ethyl acetate (12:1, v/v) to givean oil (1.45 g). The oil was crystallized by triturating with a smallamount of mixture of diisopropyl ether and diethyl ether, andrecrystallized from a mixture of diisopropyl ether (9 ml) and ethanol (1ml) to give pure crystals of 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate(840 mg), mp 114° to 115° C. An additional crop (560 mg) was recoveredfrom the filtrate by concentrating the filtrate and allowing to standthe residue in a refrigerator.

N.M.R. δ ppm (CDCl₃): 1.27 (3H, t, J=7 Hz), 2.37 (3H, s), 3.65 (2H, t),4.13 to 4.35 (4H, m), 4.5 (2H, s), 5.21 (1H, s), 7.2 to 8.1 (9H, m).

EXAMPLE 14

(1) To a cold solution of dimethyl2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(2.3 g) in methanol (46 ml) at -5° C. was added portionwise sodiumborohydride (140.7 mg) for 10 minutes, during which the temperature waskept at -4° to -5° C. with stirring. The mixture was stirred foradditional 15 minutes at -6° C. The reaction mixture was diluted withwater (20 ml) and acidified to about pH 5 with 50% acetic acid, and thencondensed under reduced pressure to separate out crystalline product.After adding water (30 ml), the crystals were collected by filtration,washed thoroughly with water and dried. Thus obtained crystals (2.05 g)were recrystallized from methanol (15 ml) to give pure crystals ofdimethyl2-methyl-4-(2-cyanophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(1.67 g), mp 177° to 178° C.

N.M.R. δ ppm (CDCl₃): 2.4 (3H, s), 3.63 (3H, s), 3.66 (3H, s), 4.8 (2H,broad s), 3.52 (1H, m), 5.35 (1H, s), 7.1 to 7.63 (4H, m).

(2) To a solution of diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(1.2 g) in ethanol (15 ml) was added portionwise sodium borohydride(62.3 mg) at 0° C. over 30 minutes with stirring. The mixture wasstirred for further 20 minutes at 0° C. The reaction mixture wasadjusted to pH 6 with 50% acetic acid and ethanol was distilled offunder reduced pressure. The residual solution was shaken with a mixtureof water and ethyl acetate, and the organic layer was separated, washedwith water, aqueous sodium bicarbonate solution and water, dried overmagnesium sulfate and evaporated to dryness under reduced pressure. Theresidual oil (1.0 g) was triturated in diethyl ether (2 ml) to givecrude crystals. Any recrystallization of the crude crystals wereresulted in insufficient purification. The recovered product (0.9 g) waschromatographed on a column of silica-gel (27 g) and eluted with amixture of benzene and ethyl acetate (7:1, v/v) to give purified oil ofdiethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(800 mg), which was crystallized and recrystallized from a mixture ofdiethyl ether and n-hexane to give pure crystals (500 mg), mp 106° to108° C.

N.M.R. δ ppm (CDCl₃): 1.05 (3H, t, J=7 Hz), 1.1 (3H, t, J=7 Hz), 2.25(3H, s), 3.90 (3H, s), 3.85 to 4.13 (2H, m), 4.71 (2H, broad s), 5.98(1H, s), 7 to 7.6 (5H, m).

(3) To a cold suspension (-2° C.) of dimethyl2-methyl-4-(2-N-methylsulfamoylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(350 mg) in methanol (7 ml) was added each one third portion of sodiumborohydride (17.85 mg) over 2 minutes with stirring. Stirring wascontinued for additional an hour and 40 minutes at -5° to -4° C., duringwhich, the reaction mixture was diluted twice with methanol; i.e. with 3ml, after 30 minutes and with 4 ml after 1 hour; and a small portion ofsodium borohydride (9 mg) was added to the reaction mixture after 1 hourand 20 minutes. Water (30 ml) was added to the reaction mixture and theresultant mixture was left to cool for 1 hour to form crystallineprecipitates. The resulting crystals (260 mg) were collected byfiltration and recrystallized from methanol (3 ml) to give dimethyl2-methyl-4-(2-N-methylsulfamoylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate,m.p. 210° to 212° C.

N.M.R. δ ppm (DMSO-d6) 2.39 (3H, s), 3.33 (3H, s), 3.59 (6H, s), 4.66(2H, broad d, J=5 Hz), 5.03 (1H, s), 5.59 (1H, broad t, J=5 Hz),7.3-7.78 (5H, m), 7.34 (1H, s), 8.6 (1H, broad s).

(4) A solution of dimethyl2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(3.60 g) in methanol (72 ml) was cooled at 0° C., and sodium borohydride(0.2271 g) was added bit by bit thereto under cooling with stirring. Themixture was stirred at the same temperature for 15 minutes. The reactionmixture was adjusted to about pH 6 with 50% acetic acid and the methanolwas distilled off under reduced pressure below 30° C. The residualsolution was diluted with water (100 ml) and extracted with ethylacetate. The extract was washed with water, an aqueous sodiumbicarbonate solution and water in turn, dried over magnesium sulfate andthen evaporated to dryness. The residual oil (3.70 g) was crystallizedby triturating with diisopropyl ether to give crude crystals (2.74 g),which were recrystallized in first from methanol (8 ml) and then fromethyl acetate (10 ml) to give pure crystals of dimethyl2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate(770 mg), mp 164.5° to 165° C. The whole mother liquor of aboverecrystallizations were combined together and concentrated. Thecrystalline residue was collected by filtration and washed with methanol(5 ml) to give additional crystals (1.72 g), which were recrystallizedfrom ethyl acetate to give additional pure specimen of the same productobtained above, (840 mg) m.p. 164.5° to 165° C. Total yield, 1.61 g.

N.M.R. δ ppm (CDCl₃): 2.33 (3H, s), 3.56 (3H, s), 3.58 (3H, s), 4.76(2H, s), 5.75 (1H, s), 7.25 to 7.75 (4H, m).

(5) A solution of isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(3.88 g) in methanol (70 ml) was cooled below -3° C., and sodiumborohydride (0.2082 g) was bit by bit added thereto with stirring. Afterstirring for further 30 minutes at -2° C., the mixture was acidifiedwith 50% acetic acid, and methanol was removed off under reducedpressure. The resultant mixture was diluted with water and extraced withethyl acetate. The extract was washed with water, a dilute aqueoussodium bicarbonate solution and water in turn, dried over magnesiumsulfate and evaporated dryness under reduced pressure to give a reddishviscous oil (4.37 g), which was triturated with a mixture of diethylether and n-hexane to give yellowish crystalline powder (3.75 g).Recrystallization form methanol (10 ml) gave yellowish granules ofisopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate(2.38 g), m.p. 135° to 137° C., which were further recrystallized fromethyl acetate (5 ml) to give the pure specimen (1.08 g), m.p. 136.5° to138° C.

N.M.R. δ ppm (CDCl₃): 0.96 (3H, d, J=6 Hz), 1.22 (3H, d, J=6 Hz), 2.38(3H, s), 3.53 (3H, s), 4.70 (2H, s), 4.94 (1H, hept., J=6 Hz), 5.83 (1H,s), ca 7.0 to 8.0 (5H, m).

(6) To a cold mixture of 2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate(1.8 g) in ethanol (36 ml) was added sodium borohydride (75.5 mg) below-3° C. and the resultant mixture was stirred at -3° to -5° C. for 40minutes. The reaction mixture was adjusted to pH 5 to 6 with 50% aceticacid and the ethanol was distilled off under reduced pressure. Theresidue was diluted with water (100 ml) to separate out crystallinemass, which were pulverized and collected by filtration. The crystals(1.57 g) were recrystallized from a mixture of diethyl ether andn-hexane. The obtained crystals (910 mg) were not pure enough toanalyze, then these were combined again with filtrate and purifiedthrough column chromatography on silica-gel column and eluted with amixture of benzene and ethyl acetate (10:1, v/v) to give an oil (1 g),which was crystallized and recrystallized from a mixture of diisopropylether and ethanol to give pure crystals of 2-benzyloxyethyl2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate(530 mg), m.p. 96° to 97° C.

N.M.R. δ ppm (CDCl₃): 1.10 (3H, t, J=7 Hz), 2.30 (3H, s), 4.47 (2H, s),3.50-4.33 (6H, m), 4.73 (2H, d, J=5 Hz), 7.05-7.75 (9H, m).

(7) To a cold suspension of dimethyl2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate(3.84 g) in methanol (76 ml) was added portionwise sodium borohydride(221.8 mg) at -7° C. over 7 minutes with stirring. Stirring wascontinued for further 5.5 hours during the course additional portion ofsodium borohydride (40 mg) was added to the reaction mixture. Theresultant mixture was diluted with water (50 ml), adjusted to pH 5 to 6with 50% aqueous acetic acid, and a small amount of insoluble substancewas filtered off. The filtrate was evaporated and the residual mixtureof solids and oils was washed with diisopropyl ether (10 ml) to givesolid product (2.7 g). The solid product was recrystallized once from amixture (20 ml) of methanol and diisopropyl ether (yield 1.78 g) andthen recrystallization from methanol (6 ml) to give pure crystals ofdimethyl2-methyl-4-(3-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.48 g), m.p. 145° to 146° C. An additional crop wasrecovered from the mother liquor of the first recrystallization byevaporating the solvent and triturating with methanol as crystallinepowder (330 mg).

N.M.R. δ ppm (CDCl₃): 2.40 (3H, s), 3.65 (6H, s), 4.81 (2H, d, J=5 Hz)5.11 (1H, s), 7.25-8.13 (6H, m).

(8) To a cold mixture of 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarboxyl-6-formyl-1,4-dihydropyridine-3-carboxylate(2.0 g) in ethanol (40 ml) was added portionwise sodium borohydride(84.1 g) at -5° C. over 3 minutes with stirring. After 35 minutes,additional sodium borohydride (8.4 mg) was added and the mixture wasstirred for further 10 minutes at -2° C. The reaction mixture wasadjusted to pH 5 to 6 with 50% aqueous acetic acid and ethanol wasdistilled off under reduced pressure. The residual mixture was dilutedwith water (100 ml) and extracted with ethyl acetate. The extract waswashed with water, dried over magnesium sulfate, and evaporated todryness under reduced pressure to give an oil which was crystallized bykeeping in a refrigerator overnight. The crystals were washed withn-hexane to give crystals (1.6 g) which were recrystallized from amixture (12 ml) of diisopropyl ether and ethanol (1:1, v/v) to give purecrystals of 2-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate(860 mg), m.p. 114.5° to 115.5° C. A second crop was recovered from themother liquor in a usual manner to yield 220 mg, m.p. 112° to 114° C.

N.M.R. δ ppm (CDCl₃): 1.20 (3H, t, J=7 Hz), 2.75 (3H, s), 3.65 (2H, t,J=3 Hz), 4.15 (2H, q, J=7 Hz), 4.24 (2H, t, J=3 Hz), 4.51 (2H, s), 4.78(2H, broad s), 5.13 (1H, s), 7.20-8.13 (9H, m).

EXAMPLE 15

(1) A mixture of methyl 4,4-dimethoxy-2-(3-nitrobenzylidene)acetoacetate(8.0 g) and isopropyl 3-aminocrotonate (4.07 g) was heated at 70° C. foran hour with stirring, and the stirring was continued at 100° C. for anhour and at 120° C. for additional 2.5 hours. After dissolving thereaction mixture in ethyl acetate, the solution was washed with waterand an aqueous solution of sodium chloride, dried over magnesium sulfateand then evaporated to dryness under reduced pressure to give ayellow-orange oil (11.03 g) of isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

    ______________________________________                                        N.M.R.  δppm (CDCl.sub.3):                                                                    1.13 (d, J = 7.0 Hz)                                                                            (6H)                                                        1.27 (d, J = 7.0 Hz)                                    2.40 (3H, s),     3.47 (s)                                                                                    (6H),                                                           3.50 (s)                                                    ______________________________________                                    

3.69 (3H, s), 5.0 (1H, heptet, J=7.0 Hz), 5.17 (1H, s), 6.04 (1H, s),6.92 (1H, broad s), 7.2-8.2 (4H, m).

(2) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylicacid was prepared by reacting methyl2-benzylidene-4,4-dimethoxyacetoacetate, which was obtained frombenzaldehyde and methyl 4,4-dimethoxyacetoacetate according to the samemanner as that of Preparation 1, with isopropyl 3-aminocrotonate insubstantially the same manner as that of Example 15-(1).

N.M.R. δppm (CDCl₃): 1.11 (3H, d, J=6.5 Hz), 1.23 (3H, d, J=6.5 Hz),2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 4.96 (1H, heptet, J=6.5 Hz),5.03 (1H, s), 6.03 (1H, s), 6.73 (1H, s), 7.0-7.4 (5H, m).

The following examples are prepared in substantially the same manner asthat of Example 15-(1).

(3) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.07 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.32 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, s),4.96 (1H, heptet, J=6.5 Hz), 5.20 (1H, s), 5.97 (1H, s), 6.65 (1H, s),6.9-7.4 (4H, m).

(4) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylicacid, mp 115°-117° C.

(5) Isopropyl ester of4-(2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 86°-87.5° C.

(6) Isopropyl ester of4-(2-trifluoromethylphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 92°-94° C.

(7) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 110°-111.5° C.

(8) Isopropyl ester of4-(2-allyloxyphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.01 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4-6.3 (8H, m), 6.60 (1H,broad s), 6.7-7.5 (4H, m).

(9) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.22 (3H, d, J=6.5 Hz), 1.28 (3H, d, J=6.5 Hz),2.37 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.76 (3H, s), 5.07 (1H,heptet, J=6.5 Hz), 5.38 (1H, s), 6.04 (1H, s), 6.65-7.45 (4H, m).

(10) Isopropyl ester of4-(2,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.07 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.34 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 4.97 (1H,heptet, J=6.5 Hz), 5.39 (1H, s), 5.96 (1H, s), 6.65 (1H, s), 7.0-7.4(3H, m).

(11) Isopropyl ester of4-(3,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃):

    ______________________________________                                        1.18 (d, J = 6.5 Hz)                                                                                       (6H),                                            1.25 (d, J = 6.5 Hz)                                                          ______________________________________                                    

2.39 (3H, s), 3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1H, s),5.00 (1H, heptet, J=6.5 Hz), 6.03 (1H, s), 6.75 (1H, s), 7.0-7.5 (3H,m).

(12) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.16 (3H, d, J=6.5 Hz), 1.25 (3H, d, J=6.5 Hz),2.37 (3H, s),

    ______________________________________                                        3.41 (s)                                                                      3.43 (s)                                                                      3.45 (s)               (6H),                                                  3.49 (s)                                                                      ______________________________________                                    

3.79 (3H, s), 3.84 (6H, s), 4.99 (1H, s), 4.99 (1H, heptet, J=6.5 Hz),6.03 (1H, s), 6.6-7.3 (4H, m).

(13) Dipropyl ester of2-methyl-4-(3-nitrophenyl)-6-dipropoxymethyl-1,4-dihydropyridine-3,5-dicarboxylicacid.

N.M.R. δppm (CDCl₃): 2.37 (3H, s), 5.02 (1H, s), 6.21 (1H, s), 6.88 (1H,broad s).

(14) 2-(N-Benzyl-N-methylamino)ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.1-1.3 (9H, m), 2.17 (3H, s), 2.33 (3H, s), 2.60(2H, t, J=6 Hz), 3.48 (2H, s), 3.4-4.4 (8H, m), 5.63 (1H, s), 6.13 (1H,s), 6.71 (1H, s), 7.1-7.6 (9H, m).

(15) 2-Phenoxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.0 to 1.5 (9H, m), 2.37 (3H, s), 3.5-4.6 (10H, m),5.67 (1H, s), 7.12 (1H, s), 6.7-7.8 (10H, m).

(16) 2-Chloroethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.0-1.5 (6H, m), 2.39 (3H, s), 3.4-4.5 (10H, m),5.5-5.7 (1H, m), 6.10 (1H, s), 6.55 (1H, s), 7-7.6 (4H, m).

(17) 2-Ethoxymethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.0-1.4 (12H, m), 2.38 (3H, s), 3.3-4.3 (12H, m),5.5-5.7 (1H, m), 6.10 (1H, s), 6.47 (1H, s), 7.2-7.7 (4H, m).

(18) 2-Benzyloxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.0-1.6 (9H, m), 2.32 (3H, s), 3.4-4.4 (10H, m),4.47 (2H, s), 5.6-5.7 (1H, m). 6.11 (1H, s), 6.6-6.8 (1H, broad s),7.2-7.7 (9H, m).

EXAMPLE 16

(1) A mixture of 2-phenoxyethyl ester of2-(2-trifluoromethylbenzylidene)acetoacetate (19.62 g) and ethyl2-amino-4,4-diethoxycrotonate (11.95 g) was heated for 20 hours at 100°to 110° C. and for additional 12 hours at 120° to 130° C. The resultantmixture was dissolved in ethyl acetate and washed with water and thendried over anhydrous magnesium sulfate. The solvent was removed bydistillation to give a crude oil (27.7 g), which was chromatographedover silica gel with a mixture of benzene and ethyl acetate (50:1 byvolume) as an eluent to give 2-phenoxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid (19.34 g).

N.M.R. δppm (CDCl₃): 1.0 to 1.5 (9H, m), 2.37 (3H, s), 3.5-4.6 (10H, m),5.67 (1H, s), 7.12 (1H, s), 6.7-7.8 (10H, m).

The following compounds were obtained in substantially the same manneras that of Example 16-(1).

(2) 2-Chloroethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.0-1.5 (6H, m), 2.39 (3H, s), 3.4-4.5 (10H, m),5.5-5.7 (1H, m), 6.10 (1H, s), 6.55 (1H, s), 7-7.6 (4H, m).

(3) 2-Ethoxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.0-1.4 (12H, m), 2.38 (3H, s), 3.3-4 3 (12H, m),5.5-5.7 (1H, m), 6.10 (1H, s), 6.47 (1H, s), 7.2-7.7 (4H, m).

(4) 2-Benzyloxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.0-1.6 (9H, m), 2.32 (3H, s), 3.4-4.4 (10H, m),4.47 (2H, s), 5.6-5.7 (1H, m), 6.11 (1H, s), 6.6-6.8 (1H, broad s),7.2-7.7 (9H, m)

(5) 2-(N-Benzyl-N-methylamino)ethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.1-1.3 (9H, m), 2.17 (3H, s), 2.33 (3H, s), 2.60(2H, t, J=6 Hz), 3.48 (2H, s), 3.4-4.4 (8H, m), 5.63 (1H, s), 6.13 (1H,s), 6.71 (1H, s), 7.1-7.6 (9H, m).

(6) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

    ______________________________________                                        N.M.R.  δppm (CDCl.sub.3):                                                                    1.13 (d, J = 7.0 Hz)                                                                            (6H),                                                       1.27 (d, J = 7.0 Hz)                                    2.40 (3H, s),     3.47 (s)                                                                                    (6H),                                                           3.50 (s)                                                    ______________________________________                                    

3.69 (3H, s), 5.0 (1H, heptet, J=7.0 Hz), 5.17 (1H, s), 6.04 (1H, s),6.92 (1H, broad s), 7.2-8.2 (4H, m).

(7) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.11 (3H, d, J=6.5 Hz), 1.23 (3H, d, J=6.5 Hz),2.37 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 4.96 (1H, heptet, J=6.5 Hz),5.03 (1H, s), 6.03 (1H, s), 6.73 (1H, s), 7.0-7.4 (5H, m).

(8) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.07 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.32 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 3.44 (3H, s), 3.62 (3H, s),4.96 (1H, heptet, J=6.5 Hz), 5.20 (1H, s), 5.97 (1H, s), 6.65 (1H, s),6.9-7.4 (4H, m).

(9) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3300, 3200, 3070, 1710 (shoulder), 1700, 1650,1603, 1518, 1278, 1269, 1190, 1090, 960, 782 cm⁻¹.

(10) Isopropyl ester of4-(2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 86°-87.5° C.

(11) Isopropyl ester of4-(2-trifluoromethylphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3400, 1720, 1690, 1653, 1493, 1319, 1310, 1278,1206, 1095, 1035, 951, 768 cm⁻¹.

(12) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 110°-111.5° C.

(13) Isopropyl ester of4-(2-allyloxyphenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.01 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4-6.3 (8H, m), 6.60 (1H,broad s), 6.7-7.5 (4H, m).

(14) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.22 (3H, d, J=6.5 Hz), 1.28 (3H, d, J=6.5 Hz),2.37 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.76 (3H, s), 5.07 (1H,heptet, J=6.5 Hz), 5.38 (1H, s), 6.04 (1H, s), 6.65-7.45 (4H, m).

(15) Isopropyl ester of4-(2,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.07 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=6.5 Hz),2.34 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 4.97 (1H,heptet, J=6.5 Hz), 5.39 (1H, s), 5.96 (1H, s), 6.65 (1H, s), 7.0-7.4(3H, m)

(16) Isopropyl ester of4-(3,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃):

    ______________________________________                                        1.18 (d, J = 6.5 Hz)                                                                                    (6H),                                               1.25 (d, J = 6.5 Hz)                                                          ______________________________________                                    

2.39 (3H, s), 3.46 (3H, s), 3.50 (3H, s), 3.70 (3H, s), 5.00 (1H, s),5.00 (1H, heptet, J=6.5 Hz), 6.03 (1H, s), 6.75 (1H, s), 7.0-7.5 (3H,m).

(17) Isopropyl ester of5-methoxycarbonyl-6-dimethoxymethyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.16 (3H, d, J=6.5 Hz), 1.25 (3H, d, J=6.5 Hz),2.37 (3H, s),

    ______________________________________                                        3.41 (s)                                                                      3.43 (s)                                                                      3.45 (s)               (6H),                                                  3.49 (s)                                                                      ______________________________________                                    

3.79 (3H, s), 3.84 (6H, s), 4.99 (1H, s), 4.99 (1H, heptet, J=6.5 Hz),6.03 (1H, s), 6.6-7.3 (4H, m).

(18) Dipropyl ester of2-methyl-4-(3-nitrophenyl)-6-dipropoxymethyl-1,4-dihydropyridine-3,5-dicarboxylicacid.

N.M.R. δppm (CDCl₃): 2.37 (3H, s), 5.02 (1H, s), 6.21 (1H, s), 6.88 (1H,broad s).

EXAMPLE 17

(1) To a solution of 2-phenoxyethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid (15.85 g) in acetone (159 ml) was added 6N hydrochloric acid (15.85ml) at ambient temperature with stirring and the stirring was continuedfor 1.5 hours. The reaction mixture was neutralized with a saturatedaqueous solution of sodium bicarbonate, and the acetone was removed invacuo. The residue was dissolved in ethyl acetate, washed with water andthen dried. Removal of the solvent gave an oil (13.56 g) of2-phenoxyethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.22 (3H, t, J=7.5 Hz), 2.40 (3H, s), 4.0-4.6 (6H,m), 5.71 (1H, s), 6.7-7.7 (10H, m), 10.26 (1H, s).

The following compounds were prepared in substantially the same manneras that of Example 17-(1).

(2) Isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylicacid.

(3) Isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylicacid, mp 143°-144° C.

(4) Isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylicacid, mp 143°-145° C.

(5) Isopropyl ester of4-(2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 102°-103° C.

(6) Isopropyl ester of4-(2-trifluoromethylphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 83°-85° C.

(7) Isopropyl ester of6-formyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 142°-143° C.

(8) Isopropyl ester of4-(2-allyloxyphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 103°-104.5° C.

(9) Isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylicacid, mp 114°-116° C.

(10) Isopropyl ester of4-(2,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.07 (3H, d, J=6.5 Hz), 1.24 (3H, d, J=6.5 Hz),2.39 (3H, s), 3.71 (3H, s), 4.98 (1H, heptet, J=6.5 Hz), 5.51 (1H, s),6.93 (1H, s), 7.0-7.4 (3H, m), 10.34 (1H, s).

(11) Isopropyl ester of4-(3,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 95°-96° C.

(12) Isopropyl ester of6-formyl-5-methoxycarbonyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.14 (3H, d, J=6.5 Hz), 1.26 (3H, d, J=6.5 Hz),2.40 (3H, s), 3.78 (3H, s), 3.84 (6H, s), 4.98 (1H, heptet, J=6.5 Hz),5.05 (1H, s), 6.5-7.3 (4H, m), 10.44 (1H, s).

(13) Dipropyl ester of6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid.

N.M.R. δppm (CDCl₃): 0.87 (3H, t, J=7.5 Hz), 0.90 (3H, t, J=7.5 Hz),1.55 (2H, sixtet, J=7.5 Hz), 1.61 (2H, sixtet, J=7.5 Hz), 2.44 (3H, s),4.02 (2H, t, J=7.5 Hz), 4.13 (2H, t, J=7.5 Hz), 5.28 (1H, s), 7.11 (1H,broad s), 7.4-8.2 (4H, m), 10.56 (1H, s).

(14) 2-Hydroxyethyl ester of5-ethoxycarbonyl-6-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicaicd.

N.M.R. δppm (CDCl₃): 5.25 (1H, s), 10.50 (1H, s).

(15) Isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.22 (3H, t, J=7.5 Hz), 2.40 (3H, s) 4.0 to 4.6(6H, m), 5.71 (1H, s), 6.7 to 7.7 (10H, m), 10.26 (1H, s).

(16) 2-Ethoxyethyl ester of5-ethoxycarbonyl-6-formyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃):

    ______________________________________                                        1.14 (t, J = 7 Hz)                                                                                      (6H),                                               1.26 (t, J = 7 Hz)                                                            ______________________________________                                    

2.43 (3H, s), 3.3-3.8 (4H, m), 4.0-4.5 (4H, m), 5.7-5.8 (1H, m), 6.8-7.0(1H, m), 7.1-7.8 (4H, m), 10.27 (1H, s).

(17) 2-Benzyloxyethyl ester of5-ethoxycarbonyl-6-formyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CCl₄): 1.23 (3H, t, J=7.5 Hz), 2.40 (3H, s), 3.4-4.5 (6H,m), 4.41 (2H, s), 5.7-5.8 (1H, m), 6.8-6.9 (1H, m), 7.2-7.8 (9H, m),10.28 (1H, s).

(18) 2-[N-Benzyl-N-methylamino]ethyl ester of5-ethoxycarbonyl-6-formyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δppm (CDCl₃): 1.23 (3H, t, J=7 Hz), 2.19 (3H, s), 2.41 (3H, s),2.63 (2H, t, J=7 Hz), 3.51 (2H, s), 4-4.4 (4H, m), 5.71 (1H, broad s),6.91 (1H, broad s), 7.2-7.7 (9H, m), 10.28 (1H, s).

EXAMPLE 18

(1) To a solution of isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate(4.2 g) in ethanol (85 ml) was gradually added portionwise sodiumborohydride (0.409 g) over a period of 35 minutes under cooling below 0°C. with stirring. After the reaction mixture was acidified with 50%aqueous solution of acetic acid, the ethanol was removed under reducedpressure. To the resultant aqueous suspension was diluted with water andthe precipitated pale-yellowish powder was collected by filtration,washed with water and dried. This powder (3.89 g) was recrystallizedwith ethanol to give a yellow powder (3.05 g) of isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 164°-166° C.

The following compounds were prepared in substantially the same manneras that of Example 18-(1).

(2) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylicacid, mp 132°-133° C.

(3) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylicacid, mp 134°-135.5° C.

(4) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylicacid, mp (182°-183° C. (dec.).

(5) Isopropyl ester of4-(2-chlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 122°-123° C.

(6) Isopropyl ester of4-(2-trifluoromethylphenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 123°-125° C.

(7) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 142°-143° C.

(8) Isopropyl ester of4-(2-allyloxyphenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 124°-125° C.

(9) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylicacid, mp 124.5°-126° C.

(10) Isopropyl ester of4-(2,4-dichlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 150°-151° C.

(11) Isopropyl ester of4-(3,4-dichlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 122°-123° C.

(12) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 123°-124° C.

(13) Dipropyl ester of6-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid, mp 118°-120° C.

(14) 2-Phenoxyethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 148°-149° C.

(15) 2-Ethoxyethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 65°-66.5° C.

(16) 2-Benzyloxyethyl ester of5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 104°-106° C.

EXAMPLE 19

(1) To a solution of isopropyl ester of6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (4.5 g) in acetic acid (35 ml) were added hydroxylaminehydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture wasstirred at ambient temperature for 2.5 hours. After acetic anhydride(4.14 g) was added to this reaction mixture, the mixture was stirred atambient temperature for 1.5 hours and at 95°-100° C. for additional 4hours. The acetic acid and the excess of acetic anhydride were removedin vacuo, followed by adding water to the residue and it was neutralizedwith a saturated aqueous solution of sodium bicarbonate. This aqueoussuspension was extracted twice with ethyl acetate, and the combinedextract was washed with water, dried over anhydrous magnesium sulfateand evaporated to dryness under reduced pressure to give a reddish-brownoil (4.88 g), which was chromatographed over silica gel (150 g) with amixture of benzene and ethyl acetate (10:1 by volume) as an eluent togive a crude crystals (2.99 g). These were recrystallized from ethanolto give yellow prisms (1.89 g) of isopropyl ester of6-cyano-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 148°-150° C.

The following compounds were prepared in substantially the same manneras that of Example 19-(1).

(2) Isopropyl ester of6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylicacid, mp 130°-131° C.

(3) Isopropyl ester of6-cyano-5-methoxycarbonyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylicacid, mp 147°-149° C.

(4) Isopropyl ester of6-cyano-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylicacid, mp 192°-195° C. (dec.).

(5) Isopropyl ester of4-(2-chlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 176°-177° C.

(6) Isopropyl ester of6-cyano-4-(2-trifluoromethylphenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 172°-173° C.

(7) Isopropyl ester of6-cyano-5-methoxycarbonyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 139°-140° C.

(8) Isopropyl ester of4-(2-allyloxyphenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 115°-116° C.

(9) Isopropyl ester of6-cyano-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylicacid, mp 129°-131° C.

(10) Isopropyl ester of4-(2,4-dichlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 141°-142° C.

(11) Isopropyl ester of4-(3,4-dichlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 159°-160° C.

(12) Isopropyl ester of6-cyano-5-methoxycarbonyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 124.5°-125.5° C.

(13) Dipropyl ester of6-cyano-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid, mp 138°-140° C.

(14) 2-Phenoxyethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 118°-119° C.

(15) 2-Hydroxyethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 150.5°-152° C.

(16) 2-Ethoxyethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 104°-105° C.

(17) 2-Benzyloxyethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 146°-147.5° C.

(18) 2-(N-Benzyl-N-methylamino)ethyl ester of6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 203°-204° C. (dec.)

EXAMPLE 20

To a solution of 2-acetoxyethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid (1.119 g) in ethanol (20 ml) was added dropwise an aqueous solution(5 ml) of potassium carbonate (0.346 g) under refluxing and stirring for2 hours.

After cooling, the ethanol was removed in vacuo from the reactionmixture, followed by neutralizing with acetic acid and extracted twicewith ethyl acetate. The combined extract was washed with diluted aqueoussolution of sodium bicarbonate and an aqueous solution of sodiumchloride, and then dried.

The solvent was removed in vacuo to give an oil, which was spontaneouslycrystallized to obtain crystals (0.94 g) of 2-hydroxyethyl ester of6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid, mp 150.5°-152° C.

EXAMPLE 21

A mixture of 2-chloroethyl ester of5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid (5.20 g), N-methyl benzylamine (3.63 g) and sodium iodide (0.2 g)in propyl alcohol (10 ml) was heated under reflux for 4.5 hours. Afterthe solvent was removed in vacuo from the reaction mixture, water andethyl acetate were added to the residue. The ethyl acetate layer wasseparated, washed with water and then dried. Removal of the solvent gavea residual oil (6.98 g), which was chromatographed over silica gel (210g) with a mixture of benzene and ethyl acetate (5:1 by volume) as aneluent to give an oil (3.67 g) of 2-(N-benzyl-N-methylamino)ethyl esterof5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm(CDCl₃): 1.1-1.3 (9H,m), 2.17(3H,s), 2.33(3H,s),2.60(2H,t,J=6 Hz), 3.48 (2H,s), 3.4-4.4(8H,m), 5.63 (1H,s), 6.13(1H,s),6.71(1H,s). 7.1-7.6 (9H,m).

EXAMPLE 22

(1) A mixture of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate(10.1 g) and isopropyl 3-aminocrotonate (5.51 g) was heated for 40minutes at 78° C. and for 5.5 hours at 120° C. with stirring, followedby heating for an hour at 125° C. without the stirring. After thereaction mixture was allowed to stand overnight, it was dissolved inethyl acetate. This solution was washed twice with water, dried and thenevaporated to dryness under reduced pressure to give a residue, whichwas crystallized from ethyl ether. The crystals were collected byfiltration and washed with a small amount of ethyl ether to give crudepowder of isopropyl ester of4-(2-cyanophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (8.96 g). Further, the crude product (0.77 g) was recovered fromthe filtrate. 0.5 g of this crude product was recrystallized fromisopropyl ether to give purified white powder of the same product (0.37g), mp 171°-172.5° C.

The following compound was obtained in the similar manner to that ofExample 22-(1).

(2) Isopropyl ester of5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm (CDCl₃): 0.95 (3H, d, J=7 Hz), 1.19 (3H, d, J=7 Hz), 2.37(3H, s), 3.40 (3H, s), 3.46 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 4.97(1H, heptet, J=7 Hz), 5.93 (1H, s), 6.05 (1H, s), 6.59 (1H, broad s7.0˜7.9 (4H, m).

EXAMPLE 23

(1) A mixture of 2-chloroethyl 2-(2-cyanobenzylidene)acetoacetate (4.72g) and ethyl 3-amino-4,4-diethoxycrotonate (4.06 g) was heated for 3hours at 100°˜105° C. with stirring. After cooling, the reaction mixturewas dissolved in ethyl acetate, and the solution was washed twice withan aqueous solution of sodium chloride and then dried over magnesiumsulfate. After removal of the solvent under reduced pressure, theresidual oil was chromatographed over silica gel with a mixture ofbenzene and ethyl acetate (5:1 V/V) to give 2-chloroethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (5.81 g).

N.M.R. δ ppm (CDCl₃): 1.1 to 1.4 (9H, m), 2.37 (3H, s), 3.4˜3.95 (6H,m), 4.0˜4.4 (4H, m), 5.39 (1H, s), 6.24 (1H, s), 6.90 (1H, broad s),7.1˜7.6 (4H, m).

The following compounds (2)˜(5) were obtained in the similar manner tothat of Example 23-(1).

(2) 2-(N-Benzyl-N-methylamino)ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm (CDCl₃): 1.1˜1.5 (9H, m), 2.21 (3H, s), 2.40 (3H, s), 2.72(2H, t, J=6 Hz), 3.53 (2H, s), 3.5˜4.5 (8H, m), 5.44 (1H, s), 6.30 (1H,s), 6.87 (1H, broad s), 7.2˜7.8 (9H, m).

(3) 2-Ethoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm (CDCl₃): 1.0˜1.5 (12H, m), 2.42 (3H, s), 3.3˜4.4 (12H, m),5.45 (1H, s), 6.30 (1H, s), 6.87 (1H, s), 7.1˜7.7 (4H, m).

(4) 2-Phenoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 94°˜95° C.

(5) 2-Benzyloxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 97.5°˜98.5° C.

EXAMPLE 24

(1) A solution of isopropyl ester of4-(2-cyanophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (9.32 g) in 6N hydrochloric acid (11 ml) and acetone (95 ml) wasstirred for 5 hours at ambient temperature. The reaction mixture wasneutralized with sodium bicarbonate and then the acetone was removed bydistillation therefrom. To the resultant solution were poured water andethyl acetate, and the ethyl acetate layer was separated, washed withwater and an aqueous solution of sodium chloride, and then dried overmagnesium sulfate. The ethyl acetate was removed by distillation underreduced pressure to give a solid, which was washed with a mixture ofethyl ether and hexane to provide crude yellowish-orange powder (7.65 g)of isopropyl ester of4-(2-cyanophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid. 0.5 g of this powder was recrystallized from isopropyl ether togive the purified yellowish-orange powder of the same product (0.34 g),mp 132°˜134° C.

The following compounds (2)˜(6) were obtained in the similar manner tothat of Example 24-(1).

(2) Isopropyl estr of6-formyl-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid

N.M.R. δ ppm (CDCl₃):

    ______________________________________                                        0.94 (d, J = 6.5 Hz)                                                                                    (6H)                                                1.19 (d, J = 6.5 Hz)                                                          ______________________________________                                    

2.41 (3H, s), 3.70 (3H, s), 3.97 (3H, s), 4.96 (1H, heptet, J=6.5 Hz),6.21 (1H, s), 6.82 (1H, broad s), 7.0˜7.9 (4H, m), 10.23 (1H, s).

(3) 2-(N-Benzyl-N-methylamino)ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm (CDCl₃): 1.29 (3H, t, J=7.5 Hz), 2.21 (3H, s), 2.44 (3H,s), 2.71 (2H, t, J=6 Hz), 3.51 (2H, s), 4.1˜4.4 (4H, m), 5.51 (1H, s),7.04 (1H, broad s), 7.2˜7.75 (9H, m), 10.57 (1H, s).

(4) 2-Ethoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 115°˜116° C.

(5) 2-Phenoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid mp 104°˜105° C.

(6) 2-Benzyloxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid.

N.M.R. δ ppm (CDCl₃): 1.28 (3H, t, J=7 Hz), 2.41 (3H, s), 3.5˜3.8 (2H,m), 4.0˜4.5 (4H, m), 4.48 (2H, s), 5.48 (1H, s), 6.9˜7.5 (10H, m), 10.51(1H, s).

EXAMPLE 25

(1) To a solution of isopropyl ester of4-(2-cyanophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (3.90 g) in acetic acid (20 ml) were added hydroxylaminehydrochloride (0.88 g) and sodium acetate (1.30 g), and the mixture wasstirred for an hour at ambient temperature. To the reaction mixture wasadded acetic anhydride (3.97 g) with stirring, and the stirring wascontinued for an hour at ambient temperature and for additional 4 hoursat 95°˜100° C. After the reaction mixture was allowed to stand atambient temperature, the acetic acid was removed by distillation underreduced pressure. The resultant residue was diluted with water,neutralized with an aqueous solution of sodium bicarbonate and thenextracted twice with ethyl acetate. After the combined extract waswashed twice with water and dried, the solvent was removed bydistillation under reduced pressure to give an oil, which was allowed tostand overnight and pulverized with a small amount of ethyl ether. Thepowder was washed with isopropyl ether and recrystallized from methanolto give yellowish-orange crystals of isopropyl ester of6-cyano-4-(2-cyanophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (1.99 g), mp 198°˜200° C.

The following compounds (2)˜(6) were obtained in the similar manner tothat of Example 25-(1).

(2) Isopropyl ester of6-cyano-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 121.5°˜123° C.

(3) 2-(N-Benzyl-N-methylamino)ethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid hydrochloride, mp 230° C. (dec.).

(4) 2-Ethoxyethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 135°˜136° C.

(5) 2-Phenoxyethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 170.5°˜172° C.

(6) 2-Benzyloxyethyl ester of6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 132°˜133° C.

EXAMPLE 26

(1) To a solution of isopropyl ester of4-(2-cyanophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (3.2 g) in ethanol (65 ml) was added dropwise sodium borohydride(0.33 g) over a period of 10 minutes under cooling at 0° C. withstirring, and the stirring was continued for an hour at the sametemperature. After the reaction mixture was slightly acidified with 50%aqueous acetic acid under cooling at 0° C., the ethanol was removed bydistillation under reduced pressure. The resultant residue was dilutedwith water, neutralized with sodium bicarbonate and extracted twice withethyl acetate. The combined extract was washed with water, an aqueoussolution of sodium chloride, and then dried. The solvent was removed bydistillation under reduced pressure to give a viscous yellowish oil(3.75 g), which was pulverized with a mixture of ethyl ether and hexane.This powder (3.19 g) was recrystallized from isopropyl ether containinga small amount of methanol to give pale-yellowish crystals of isopropylester of4-(2-cyanophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (1.97 g), mp 135°˜137° C.

The following compounds (2)˜(5) were obtained in the similar manner tothat of Example 26-(1).

(2) Isopropyl ester of6-hydroxymethyl-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 144°˜145° C.

(3) 2-Ethoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 127.5°˜128.5° C.

(4) 2-Phenoxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 116°˜117° C.

(5) 2-Benzyloxyethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid, mp 109°˜110° C.

EXAMPLE 27

To a mixture of 2-chloroethyl ester of5-ethoxycarbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (5.81 g) and N-benzyl-N-methylamine (5.78 g) in n-propyl alcohol(10 ml) was added a catalytic amount of sodium iodide (0.2 g), and themixture was refluxed for 4 hours under heating with stirring. Aftercooling, the solvent was removed by distillation from the reactionmixture under reduced pressure to give a residue, which was dissolved ina mixture of ethyl acetate and water. The separated organic layer waswashed several times with water and then dried. Removal of the solventgave brownish oil, which was purified by column chromatography on silicagel (230 g) with a mixture of benzene and ethyl acetate (5:2 v/v) as aneluent to give 2-(N-benzyl-N-methylamino)ethyl ester of4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylicacid (5.10 g).

N.M.R. δ ppm (CDCl₃): 1.1˜1.5 (9H, m), 2.21 (3H, s), 2.40 (3H, s), 2.72(2H, t, J=6 Hz), 3.53 (2H, s), 3.5˜4.5 (8H, m), 5.44 (1H, s), 6.30 (1H,s), 6.87 (1H, broad s), 7.2˜7.8 (9H, m).

EXAMPLE 28

A mixture of methyl 2-(2-cyanobenzylidine)-4,4-dimethoxyacetoacetate(11.12 g) and n-propyl 3-aminocrotonate (7.53 g) was stirred at 67° C.for 4 hours, and the stirring was continued at 95.5° C. for 14 hours andat 102° C. for additional 15 hours. The reaction mixture (11.83 g) wasdissolved in a proper quantity of diisopropyl ether, and chromatographedon silica gel (300 g) with methylene chloride as an eluent. Fractionscontaining a desired compound were collected. The solvent was distilledoff from the eluate under reduced pressure to give pale yellowishcrystals (1.45 g) of n-propyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate,mp 139°-141° C.

N.M.R. δ ppm (CDCl₃): 1.78 (3H, t, J=7.3 Hz). 1.64 (2H, sixtet, J=7.3Hz), 2.42 (3H, s), 3.47 (3H, s), 3.52 (3H, s), 3.73 (3H, s), 4.04 (2H,t, J=7.3 Hz), 5.42 (1H, s), 6.08 (1H, s), 6.77 (1H, m), 7.13-7.38 (1H,m), 7.38-7.71 (3H, m).

EXAMPLE 29

Isobutyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(17.38 g) was obtained by heating a mixture of methyl2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.82 g) and isobutyl3-aminocrotonate (8.47 g) in substantially the same manner as that ofExample 28, mp 126°-128° C.

N.M.R. δ ppm (CDCl₃): 0.74 (3H, d, J=6.5 Hz), 0.87 (3H, d, J=6.5 Hz),2.02 (1H, m), 2.41 (3H, s), 3.47 (3H, s), 3.52 (3H, s), 3.73 (3H, s),3.87 (2H, d, J=6.5 Hz), 5.42 (1H, s), 6.06 (1H, s), 6.76 (1H, m),7.13-7.43 (1H, m), 7.43-7.68 (3H, m).

EXAMPLE 30

Neopentyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(8.53 g) was obtained by heating a mixture of methyl2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.37 g) and neopentyl3-aminocrotonate (8.60 g) in substantially the same manner as that ofExample 28, mp 130°-131° C.

N.M.R. δppm (CDCl₃): 0.85 (9H, s), 2.36 (3H, s), 3.42 (3H, s), 3.46 (3H,s), 3.67 (3H, s), 3.80 (2H, s), 5.37 (1H, s), 6.00 (1H, s), 6.75 (1H,m), 7.00-7.35 (1H, m), 7.35-7.65 (3H, m).

EXAMPLE 31

To a solution (132 ml) of n-propyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(13.28 g) in acetone was added dropwise 6N hydrochloric acid (13.2 ml)at 12° C. with stirring, and the stirring was continued for 5.5 hours.The resultant mixture was adjusted to about pH 7 with an aqueous sodiumbicarbonate solution. The acetone was distilled off under reducedpressure. The precipitated crystals were collected by filtration andwashed with an aqueous sodium chloride solution, water and petroleumether, successively, and then recrystallized from a mixture of benzeneand n-hexane. The crystals were collected by filtration and washed withdiethyl ether to give n-propyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(3.37 g), mp 137.5°-141.0° C.

The mother liquor of the above recrystallization was evaporated todryness and the residue was chromatographed on silica gel (240 g) withmethylene chloride as an eluent to recover the above same product (3.83g). Total yield was 7.2 g.

N.M.R. δppm (CDCl₃): 0.78 (3H, t, J=7 Hz), 1.63 (2H, sixtet, J=7 Hz),2.43 (3H, s), 3.77 (3H, s), 4.02 (2H, t, J=7 Hz), 5.45 (1H, s), 6.95(1H, m), 7.2-7.8 (4H, m), 10.51 (1H, s).

EXAMPLE 32

Isobutyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(6.82 g) was obtained by reacting isobutyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(20.37 g) with 6N hydrochloric acid (14 ml) in substantially the samemanner as that of Example 31, mp 152.5°-154.5° C.

N.M.R. δppm (CDCl₃): 0.76 (3H, d, J=6.5 Hz), 0.82 (3H, d, J=6.5 Hz),2.02 (1H, m), 2.46 (3H, s), 3.83 (3H, s), 3.90 (2H, d, J=6.5 Hz), 5.53(1H, s), 7.0 (1H, m), 7.2-7.8 (4H, m), 10.55 (1H, s).

EXAMPLE 33

Neopentyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(5.83 g) was obtained by reacting neopentyl6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(15.56 g) with 6N hydrochloric acid (14.2 ml) in substantially the samemanner as that of Example 31, mp 141.0°-143.0° C.

N.M.R. δppm (CDCl₃): 0.86 (9H, s), 2.43 (3H, s), 3.80 (3H, s), 3.85 (2H,s), 5.49 (1H, s), 7.00 (1H, m), 7.3-7.7 (4H, m), 10.50 (1H, s)

EXAMPLE 34

A mixture of n-propyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(4.29 g), hydroxylamine hydrochloride (0.87 g), sodium acetate (1.13 g)and acetic acid (26 ml) was stirred at ambient temperature for 5 hours.To this mixture was added acetic anhydride (5 g), followed by stirringat ambient temperature for 80 minutes, at 85° C. for 2.5 hours and at93° C. for additional 9.5 hours. After cooling, the solvent was removedfrom the reaction mixture under reduced pressure, and to the residuewere added an aqueous solution of sodium bicarbonate and methylenechloride. The separated organic layer was washed with water, dried andthen evaporated to dryness to give a residue (3.42 g), which waschromatographed on silica gel (100 g) with methylene chloride as aneluent and desired fractions were collected and evaporated. Theresultant residue was recrystallized twice from a mixed solvent ofmethanol and water and then from methylene chloride to give purecrystals (2.29 g) of n-propyl6-cyano-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate,mp 150.0° -151.5° C.

N.M.R. δppm (CDCl₃): 0.77 (3H, t, J=7 Hz), 1.59 (2H, sixtet, J=7 Hz),2.37 (3H, s), 3.74 (3H, s), 3.98 (2H, t, J=7 Hz), 5.38 (1H, s), 6.85(1H, m), 7.0-7.7 (4H, m).

EXAMPLE 35

Isobutyl6-cyano-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(1.81 g) was obtained by reacting isobutyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(3.39 g) with hydroxylamine hydrochloride (0.89 g), sodium acetate (1.12g), acetic acid (25 ml) and acetic anhydride (6.24 g) in substantiallythe same manner as that of Example 34, mp 196.0°-197.5° C.

N.M.R. δppm (CDCl₃): 0.75 (3H, d, J=7 Hz), 0.81 (3H, d, J=7 Hz), 1.97(1H, m), 2.40 (3H, s), 3.78 (3H, s), 3.85 (2H, d, J=7 Hz), 5.41 (1H, s),7.02 (1H, m), 7.19-7.68 (4H, m).

EXAMPLE 36

Neopentyl6-cyano-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(1.69 g) was obtained by reacting neopentyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(3.78 g) with hydroxylamine hydrochloride (0.97 g), sodium acetate (1.19g), acetic acid (25 ml) and acetic anhydride (6.4 g) in substantiallythe same manner as that of Example 34, mp 173.0°-174.0° C.

N.M.R. δppm (CDCl₃): 0.87 (9H, s), 2.41 (3H, s), 3.79 (3H, s), 3.84 (2H,s), 5.44 (1H, s), 6.85 (1H, m), 7.2-7.8 (4H, m).

EXAMPLE 37

To a suspension of n-propyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropropyridine-3-carboxylate(2.00 g) in ethanol (40 ml) was added sodium borohydride (0.17 g) at -5°to -10° C. over a period of 5 minutes with stirring, and the stirringwas continued at the same temperature for 2 hours. To the reactionmixture was added 50% acetic acid (0.6 ml), followed by removal of thesolvent under reduced pressure. The residue was dissolved in ethylacetate, washed with an aqueous solution of sodium chloride and thendried. The solution was evaporated to give crude crystals (2.04 g),which were recrystallized from a mixed solvent of methanol and water togive pure product (1.34 g) of n-propyl6-hydroxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate,mp 149.0°-152.5° C.

N.M.R. δppm (CDCl₃): 0.77 (3H, t, J=7 Hz), 1.61 (2H, sixtet, J=7 Hz),2.38 (3H, s), 3.63 (3H, s), 3.99 (2H, t, J=7 Hz), 4.79 (2H, s), 5.31(1H, s), 7.32 (1H, m), 7.1-7.6 (4H, m).

EXAMPLE 38

Isopropyl6-hydroxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(1.49 g) was obtained by reacting isopropyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(2.00 g) with sodium borohydride (0.18 g) in substantially the samemanner as that of Example 37, mp 134.5°-137.0° C.

N.M.R. δppm (CDCl₃): 0.75 (3H, d, J=7 Hz), 0.81 (3H, d, J=7 Hz), 1.97(1H, m), 2.39 (3H, s), 2.8 (1H, m), 3.64 (3H, s), 3.86 (2H, d, J=7 Hz),4.81 (2H, s), 5.35 (1H, s), 7.1-7.7 (5H, m).

EXAMPLE 39

Neopentyl6-hydroxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(1.54 g) was obtained by reacting neopentyl6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate(2.00 g) with sodium borohydride (0.16 g) in substantially the samemanner as that of Example 37, mp 178.0°-179.5° C.

N.M.R. δppm (CDCl₃): 0.87 (9H, s), 2.38 (3H, s), 3.63 (3H, s), 3.81 (2H,s), 4.78 (2H, s), 5.33 (1H, s), 7.37 (1H, m), 7.1-7.6 (4H, m).

PREPARATION OF THE STARTING COMPOUNDS

Preparation 1

(1) To a solution of 3-nitrobenzaldehyde (7.56 g) and methyl4,4-dimethoxyacetoacetate (7.93 g) in dried benzene (30 ml) were addedacetic acid (0.18 g) and piperidine (0.17 g), and the mixture was heatedunder reflux for 3.5 hours, while azeotropically removing the waterformed therefrom. After adding benzene to the reaction mixture, thesolution was washed successively with water, diluted aqueous solution ofsodium bicarbonate, water and a saturated aqueous solution of sodiumchloride, in turn and then dried. Removal of the solvent under reducedpressure gave an oily residue (15.74 g), which was chromatographed oversilica gel (470 g) with a mixture of benzene and ethyl acetate (25:1 byvolume as an eluent to give a yellow oil (8.06 g) of methyl4,4-dimethoxy-2-(3-nitrobenzylidene)acetoacetate (a mixture of cis andtrans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.45 (s)                                                                                        (6H),                                                       3.48 (s)                                                      3.88 (s)                4.90 (s)                                                              (3H)                  (1H),                                   3.91 (s)                5.08 (s)                                              7.25-8.4 (5H, m).                                                             ______________________________________                                    

The following compounds were obtained in substantially the same manneras that of Preparation 1.

(2) Methyl 4,4-dimethoxy-2-(2-methylbenzylidene)acetoacetate (a mixtureof cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                             2.33 (3H, s),                                                                             3.23 (s)                                                                                  (6H),                                                             3.42 (s)                                           3.64 (s)               4.53 (s)                                                               (3H),             (1H),                                       3.79 (s)               5.04 (s)                                               6.8-7.4 (4H, m),                                                                             7.97 (s)                                                                                     (1H)                                                           8.09 (s)                                                       ______________________________________                                    

(3) Methyl 2-(2-chlorobenzylidine)-4,4-dimethoxyacetoacetate (a mixtureof cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.28 (s)                                                                                        (6H),                                                       3.41 (s)                                                      3.71 (s)                4.68 (s)                                                              (3H),                 (1H),                                   3.81 (s)                5.08 (s)                                              7-7.5 (4H, m),  8.02 (s)                                                                                        (1H).                                                       8.12 (s)                                                      ______________________________________                                    

(4) Methyl 4,4-dimethoxy-2-(4-pyridylmethylene)acetoacetate (a mixtureof cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.41 (s)                                                                                        (6H),                                                       3.48 (s)                                                      3.82 (s)                4.82 (s)                                                              (3H),                 (1H),                                   3.89 (s)                5.06 (s)                                              7.1-7.4 (2H, m),                                                                              7.73 (s)                                                                                        (1H),                                                       7.83 (s)                                                      8.5-8.8 (2H, m).                                                              ______________________________________                                    

(5) Methyl 2-(2-trifluoromethylbenzylidene)-4,4-dimethoxyacetoacetate (amixture of cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.28 (s)                                                                                        (6H),                                                       3.42 (s)                                                      3.61 (s)                4.62 (s)                                                              (3H),                 (1H),                                   3.84 (s)                5.06 (s)                                              7.2-7.8 (4H, m),                                                                              8.0-8.14 (1H, m).                                             ______________________________________                                    

(6) Methyl 4,4-dimethoxy-2-(2-methoxybenzylidene)acetoacetate (a mixtureof cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.39 (s)                                                                                        (6H),                                                       3.47 (s)                                                      3.78 (s)                4.77 (s)                                                              (6H),                 (1H),                                   3.88 (s)                5.16 (s)                                              6.7-7.2 (m)               8.15 (s)                                                              (4H),                 (1H).                                 7.3-7.9 (m)               8.23 (s)                                            ______________________________________                                    

(7) Methyl 2-(2-allyloxybenzylidine)-4,4-dimethoxyacetoacetate (amixture of cis and trans isomers).

    ______________________________________                                        N.M.R. δ ppm (CDCl.sub.3):                                                              3.3 (s)                                                                                         (6H),                                                       3.4 (s)                                                       3.73(s)                 4.54 (2H, m),                                                         (3H),                                                         3.78 (s)                                                                      4.71 (s)                5.1-5.5 (2H, m),                                                      (1H),                                                         5.07 (s)                                                                      5.8-6.22 (1H, m),                                                                             6.7-7.0 (m)                                                                                     (4H),                                                       7.2-7.4 (m)                                                   8.14 (s)                                                                                      (1H).                                                         8.23 (s)                                                                      ______________________________________                                    

(8) Methyl 4,4-dimethoxy-2-(2-thenylidene)acetoacetate (a mixture of cisand trans isomers).

    ______________________________________                                        N.M.R. δppm (CDCl.sub.3):                                                                  3.45 (6H, s),                                                                              3.88 (s)                                                                                (3H),                               5.11 (s)                7-7.8 (3H, m),                                                                          3.95 (s)                                                     (1H),                                                        5.17 (s)                                                                      7.93 (s)                                                                                       (1H).                                                        8.06 (s)                                                                      ______________________________________                                    

(9) Methyl 2-(2,4-dichlorobenzylidine)-4,4-dimethoxyacetoacetate (amixture of cis and trans isomers).

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                      3.39 (s)                                                                                   (6H),                                                            3.47 (s)                                                    3.77 (s)              4.77 (s)                                                            (3H),                (1H),                                        3.88 (s)              5.01 (s)                                                7.2-7.5     (3H, m),  7.97 (s)                                                                                 (1H).                                                              8.08 (s)                                        ______________________________________                                    

(10) Methyl 2-(3,4-dichlorobenzylidene)-4,4-dimethoxyacetoacetate (oneof cis and trans isomers), mp 86.5°-87.5° C.

(11) Methyl 4,4-dimethoxy-2-(3,4-dimethoxybenzylidene)acetoacetate (amixture of cis and trans isomers).

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                      3.43 (s)                                                                                   (6H),                                                            3.49 (s)                                                    3.87 (s)              4.87 (s)                                                3.92 (s)                         (1H),                                                    (9H),     5.10 (s)                                                3.93 (s)                                                                      3.97 (s)                                                                      6.6-7.4     (3H, m),  7.80 (s)                                                                                 (1H).                                                              7.89 (s)                                        ______________________________________                                    

(12) 2-Phenoxyethylester of 2-(2-trifluoromethylbenzylidene)acetoaceticacid (a mixture of cis and trans isomers).

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                    2.18 (s)                                                                                    (3H),                                                           2.47 (s)                                                        3.9-4.9 (4H, m),                                                                            6.8-8.2       (10H, m).                               ______________________________________                                    

(13) 2-Chloroethyl ester of 2-(2-trifluoromethylbenzylidene)acetoaceticacid (a mixture of cis and trans isomers).

    ______________________________________                                        N.M.R. δppm (CDCl.sub.3):                                                                          2.18 (s)                                                                                (3H),                                                               2.46 (s)                                                  3.50 (t, J = 6 Hz)                                                                                (2H),                                                     3.76 (t, J = 6 Hz)                                                            4.34 (t, J = 6 Hz)            7.3-7.9 (4H, m),                                                    (2H),                                                     4.51 (t, J = 6 Hz)                                                            7.95 (q, J = 2.2 Hz)                                                                              (1H).                                                     8.04 (q, J = 2.2 Hz)                                                   ______________________________________                                    

(14) 2-Ethoxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoaceticacid (a mixture of cis and trans isomers).

    ______________________________________                                        N.M.R. δppm (CCl.sub.4 ):                                                                   1.10 (t, J = 7 Hz)                                                                              (3H),                                                       1.18 (t, J = 7 Hz)                                        2.11 (s)                 3.1-3.8 (4H, m),                                                      (3H),                                                        2.38 (s)                                                                      4.1-4.5    (2H, m),  7.3-8.0 (5H, m).                                         ______________________________________                                    

(15) 2-Benzyloxyethyl ester of2-(2-trifluoromethylbenzylidene)acetoacetic acid (a mixture of cis andtrans isomers).

    ______________________________________                                        N.M.R. δppm (CCl.sub.4 ):                                                                   2.10 (s)         3.4-3.9 (2H, m),                                                         (3H),                                                             2.37 (s)                                                  4.1-4.7 (m)                 7.2-8.0 (10H, m)                                  4.37 (s)            (4H),                                                     4.53 (s)                                                                      ______________________________________                                    

Preparation 2

(1) A solution of 2-cyanobenzaldehyde (6.56 g), methyl4,4-dimethoxyacetoacetate (7.93 g), acetic acid (0.18 g) and piperidine(0.17 g) in benzene (40 ml) was refluxed for 5 hours with stirring underazeotropic dehydration. After cooling, the reaction mixture was dilutedwith benzene, washed with water, an aqueous solution of sodiumbicarbonate, and then dried over magnesium sulfate. After removal of thesolvent, the residual oil (13.75 g) was subjected to columnchromatography on silica gel (420 g) with a mixture of benzene and ethylacetate (20:1 V/V) as an eluent. The fractions containing a desiredcompound were collected and the solvent was removed by distillationunder reduced pressure to give a yellowish oil of methyl2-(2-cyanobenzylidene)-4,4-dimethoxy acetoacetate (a mixture of cis andtrans isomers) (10.11 g).

    ______________________________________                                        N.M.R.                                                                        δppm (CDCl.sub.3):                                                                  3.41 (s)            3.79 (s)                                                                 (6H),           (3H),                                          3.49 (s)            3.92 (s)                                      4.83 (s)                       8.07(s)                                                        (1H), 7.5˜8.0 (4H, m),                                                                           (1H)                                 5.11 (s)                       8.16 (s)                                       ______________________________________                                    

The following starting compounds (2)˜(6) were obtained in the similarmanner to that of Preparation 2-(1).

(2) Methyl 2-(2-methoxycarbonylbenzylidene)-4,4-dimethoxyacetoacetate (amixture of cis and trans isomers)

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                   3.26 (s)                                                                                    (6H)                                                            3.43 (s)                                                                      3.56 (s)                                                                      3.83 (s)                                                                      3.87 (s)      (6H)                                                            3.89 (s)                                                                      4.67 (s)                                                                                    (1H)                                                            5.13 (s)                                                                      7.2˜8.1 (4H, m)                                                         8.39 (s)                                                                                    (1H)                                                            8.46 (s)                                               ______________________________________                                    

(3) 2-Chloroethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture of cisand trans isomers).

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                   2.34 (s)                                                                                    (3H)                                                            2.50 (s)                                                                      3.6˜3.9 (2H, m)                                                         4.3˜4.6 (2H, m)                                                         7.25˜7.9                                                                              (4H, m)                                                         8.00 (s)                                                                                    (1H)                                                            7.88 (s)                                               ______________________________________                                    

(4) 2-Ethoxyethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture of cisand trans isomers).

    ______________________________________                                        N.M.R. δppm (CDCl.sub.3):                                                                  1.15 (t, J = 6.5 Hz)                                                                              (3H)                                                      1.23 (t, J = 6.5 Hz)                                                    2.35 (s)                                                                                  (3H)                                                              2.48 (s)                                                                      3.58 (2H, q, J = 6.5 Hz)                                                      3.7˜3.8                                                                           (2H, m)                                                             4.3˜4.5                                                                          (2H, m)                                                              7.30˜8.05                                                                        (4H, m)                                                              7.95 (s)                                                                                  (1H)                                                              7.91 (s)                                                         ______________________________________                                    

(5) 2-Phenoxyethyl 2-(2-cyanobenzylidene)acetoacetate (one of cis andtrans isomers), mp 102.5°˜104° C.

(6) 2-Benzyloxyethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture ofcis and trans isomers).

    ______________________________________                                        N.M.R.    δppm (CDCl.sub.3):                                                                   2.29 (s)                                                                                     (3H),                                                          2.43 (s)                                                                      3.50˜3.85                                                                              (2H, m)                                                        4.20˜4.60                                                                              (2H, m)                                                        4.55 (s)                                                                                     (2H)                                                           4.44 (s)                                                                      7.15˜7.85                                                                              (9H, m)                                                        7.96 (s)                                                                                     (1H)                                                           7.83 (s)                                               ______________________________________                                    

Preparation 3

A benzene solution (120 ml) of 2-cyanobenzaldehyde (30.97 g), methyl4,4-dimethoxyacetoacetate (46.14 g), acetic acid (2.3 g) and piperidine(2.4 g) was refluxed under heating for 8 hours. After addition ofbenzene (80 ml) and washing with water, the solution was treated with anactivated charcoal. The evaporated residue was chromatographed on silicagel (500 g) with methylene chloride as an eluent. The fractionscontaining a desired compound were collected and evaporated to givemethyl 2-(2-cyanobenzylidine)-4,4-dimethoxyacetoacetate (25.16 g).

    ______________________________________                                        N.M.R. δppm (CDCl.sub.3):                                                                  3.41 (s)         3.69 (s)                                                                 (6H),          (3H),                                              3.50 (s)         3.92 (s)                                  4.83 (s)                    7.40-7.90 (4H, m),                                                     (1H),                                                    5.10 (s)                                                                      8.04 (s)                                                                                           (1H)                                                     8.17 (s)                                                                      ______________________________________                                    

I claim:
 1. A compound of the formula: ##STR28## wherein R₁ isunsubstituted phenyl, monosubstituted phenyl wherein the substitutent isselected from halogen, nitro, trifluoromethyl, lower alkoxy, loweralkenyloxy, cyano, methyl and lower alkoxycarbonyl, disubstituted phenylwherein the substituents are selected from 2-chloro-5-nitro,2,4-dichloro, 3,4-dichloro and 3,4-dimethoxy,R₂ is lower alkoxycarbonyl,R₃ is lower alkoxycarbonyl, hydroxy(lower)alkoxycarbonyl, loweralkoxy(lower)alkoxycarbonyl, phenyl(lower)alkoxy(lower)alkoxycarbonyl,phenoxy(lower)alkoxycarbonyl,N,N-di(lower)alkylamino(lower)alkoxycarbonyl, or N-loweralkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl, R₄ ishydroxyimino(lower)alkyl, and R₅ is lower alkyl.
 2. A compound accordingto claim 1, wherein R₁ is phenyl, nitrophenyl, halophenyl,2-halo-5-nitrodisubstituted phenyl, trifluoromethylphenyl, loweralkenyloxyphenyl, cyanophenyl or lower alkoxycarbonylphenyl R₃ is loweralkoxycarbonyl, lower alkoxy(lower)alkoxycarbonyl,phenyl(lower)alkoxy(lower)alkoxycarbonyl, phenoxy(lower)alkoxycarbonyl,N,N-di(lower)alkylamino(lower)alkoxycarbonyl orN-(lower)alkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl.
 3. Acompound according to claim 2 that is diethyl2-methyl-4-(2-chlorophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.4. A compound according to claim 2 that is diethyl2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.5. A compound according to claim 2 that is diethyl2-methyl-4-(3-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.6. A compound according to claim 2 that is diethyl2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.7. A compound according to claim 2 that is diethyl4-(2-chloro-5-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.8. A compound according to claim 2 that is dimethyl2-methyl-4-(2-cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.9. A compound according to claim 2 that is diethyl2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.10. A compound according to claim 2 that is dimethyl2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.11. A compound according to claim 2 that is isopropyl2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.12. A compound according to claim 2 that is dimethyl2-methyl-4-(3-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.13. A compound according to claim 2 that is 3-benzyloxyethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.14. A compound according to claim 2, whereinR₁ is 3-nitrophenyl, R₃ islower alkoxycarbonyl, lower alkoxy(lower)alkoxycarbonyl,N,N-di(lower)alkylamino(lower)alkoxycarbonyl or N-loweralkyl-N-phenyl(lower)alkylamino(lower)alkoxycarbonyl, R₄ ishydroxyiminomethyl, and R₅ is methyl.
 15. A compound of claim 1 that is3-(N-methyl-N-benzylamino)ethyl2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate.16. A compound according to claim 14, wherein R₂ is ethoxycarbonyl, andR₃ is 2-ethoxyethoxycarbonyl, 2-(N,N-diethylamino)ethoxycarbonyl or2-(N-methyl-N-benzylamino)ethoxycarbonyl.
 17. A method for effectingvasodilation in humans and mammals which comprises administering theretoan effective amount of the compound of claim
 1. 18. A method foreffecting vasodilation in humans and mammals which comprisesadministering thereto an oral daily dose of 0.1 to 500 mg. or 10 to 25%thereof intravenously of the compound of claim
 1. 19. A method foreffecting vasodilation in humans and mammals which comprisesadministering thereto an oral daily dose of 1 to 50 mg. or 10 to 25%thereof intravenously of the compound of claim
 1. 20. A method foreffecting vasodilation in humans and mammals which comprisesadministering thereto an oral daily dose of 1 μg to 10 mg/kg. or 10 to25% thereof intravenously of the compound of claim
 1. 21. A method foreffecting vasodilation in humans and mammals which comprisesadministering thereto an oral daily dose of 0.5 to 5 mg/kg or 10 to 25%thereof intravenously of the compound of claim 1.